JP6911033B2 - Chiral division method of N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative using polar aprotic solvent - Google Patents

Description

The present specification discloses a method for chiral division of an N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative.

In recent years, the demand for sterically pure compounds has been increasing rapidly. One important use for such pure stereoisomers is as an intermediate for synthesis in the pharmaceutical industry. For example, it is becoming increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. Such advantages include fewer side effects and higher efficacy often associated with enantiomerically pure compounds [Non-Patent Document 1].

For example, there are four isomers of Triadimenol, but the (-)-(1S, 2R) -isomer is the (+)-(1R, 2R) -isomer, and (-)-. The (1S, 2S) -isomers are more active than the (+)-(1R, 2S) -isomers, respectively. Dichloromethane is known to have the highest activity of the (1R, 2R) -isomer among the four isomers. It is also known that the (+)-(2S, 4S)-and (-)-(2S, 4R) -isomers of etaconazole also have a higher bactericidal effect than other isomers.

Therefore, if only one highly active isomer can be selectively produced, a high effect can be obtained by using a small amount, and as a result, environmental pollution due to the use of chemical substances can be reduced. There is an advantage. In particular, in the case of pharmaceuticals, when one isomer is toxic to the human body, it is very important to selectively produce only another isomer.

Therefore, in fields such as pharmaceuticals, pharmaceuticals, and biochemistry-related industries, it is extremely important to dispense optically pure compounds for the purpose of improving drug efficacy per unit and preventing phytotoxicity due to side effects. ..

For example, vanilloid antagonists containing N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivatives have been shown to be effective against pure stereoisomers [Patent Documents 1 to 4].

As a synthetic method for producing a single isomer for such an N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative, an asymmetric synthesis method using an Ermann auxiliary is known. .. As an example, Patent Documents 1 to 4 present a method capable of obtaining a desired steric isomer by introducing an Elman auxiliary and inducing an asymmetric reduction utilizing the auxiliary. However, in such a method, it is necessary to keep the reaction system at a low temperature in order to increase the optical purity (enantiomeric excess,% ee), and there is a risk of excessive hydrogen generation and heat generation in the process of cooling the reaction system. In addition, excessive organic and inorganic waste is generated after cooling of the reaction system, which limits the treatment process and economic aspects.

International Publication No. 2008/013414 A1 Gazette International Publication No. 2007/133637 A2 Gazette International Publication No. 2007/129188 A1 Gazette International Publication No. 2010/010934 A1 Gazette

Stephen C. Stinson, “In wake of new FDA guidelines, most drug firms are developing single enantiomers, spawning a“ chirotechnology ”industry”, Chem. Eng. News, 1992, 70 (39), pp 46-79

Although prior art relating to the asymmetric synthesis method of N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative has been reported, the manufacturing method for commercial use is economical and safe. Therefore, it has not been established yet. Therefore, the present specification is a method that solves the problems of the above-mentioned conventional asymmetric synthesis method and also considers economic efficiency and process safety, and uses a stereoisomer mixture and a polar aprotic solvent. It is intended to provide a new method of chiral division using.

In order to achieve the above object, the present invention has an optical activity of an N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative having a structure represented by the following chemical formula 1 in one aspect. Provided is a method for separating an N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative salt into each compound having high optical purity using a chiral auxiliary.

More specifically, (R, S) -N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative and an optically active chiral auxiliary are mixed in a polar aprotonic solvent (R). -Or (S) -type optically active N- [4- (1-aminoethyl) -phenyl] -sulfonamide diacyl tartrate or a solvent mixture thereof, and then produced optically active N- [4- It comprises the process of liberating a (1-aminoethyl) -phenyl] -sulfonamide salt or a sulfonamide with a base to produce optically active N- [4- (1-aminoethyl) -phenyl] -sulfonamide (R). , S) -N- [4- (1-aminoethyl) -phenyl] -sulfonamide to N- [4- (1-aminoethyl) -phenyl] -sulfonamide with high optical purity.

According to such a method, the N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative can be easily chirally divided into the respective compounds having high optical purity.

N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide is a generic name for a compound represented by the following chemical formula 2, and is a TRPV1 (transient receptor potential cation channel subfamily V member). 1 or capacin receptor, vanilloid receptor 1) It is known to be useful as an intermediate for producing a compound that acts as an antagonist.

As shown by the chemical formula 2, N- [4- (1-aminoethyl) -difluorophenyl] -methanesulfonamide is a chiral compound in which a carbon bonded to an amine group exists as a chiral center. be.

According to the chiral division method according to one aspect of the present invention, a stereoisomer mixture, particularly a stereoisomer mixture of a compound in which an amine group is bonded to an asymmetric carbon atom, is easily chirally divided into a compound having high optical purity. can do. Such a method is a synthesis method in which safety and economy at the time of manufacture are improved as compared with an asymmetric synthesis method using an Elman auxiliary, and chiral division is performed with an optical purity equal to or higher than that of the method. It shows high economic efficiency and environmental friendliness by recovering and reusing salt. Therefore, such a method can be effectively used in the production of raw materials in the fields of pharmacy and cosmetics, which require chiral division of compounds.

In particular, the method according to one aspect of the present invention is a production method with higher efficiency than the conventional asymmetric synthesis method using an Elman auxiliary, and optics of a desired stereoisomer equal to or higher than that of the conventional method. It can be obtained with purity and shows high efficiency and economic effect in terms of mass production.

Further, according to the method according to one aspect of the present invention, the mother liquor of the stereoisomer mixture is adjusted or converted into a racemate in which the S-isomer and the R-isomer are mixed at a ratio of about 1: 1. Is possible. Racemization can be performed only by the process of chiralizing a stereoisomer compound with high purity without using a separate racemization reaction. Therefore, according to the method according to one aspect of the present invention, the mother liquor can be directly used in another chiral division step without going through a separate step, and as a result, unlike a general racemization reaction, a compound can be produced. It can be used economically without loss.

In one aspect, the invention comprises mixing a stereoisomeric mixture of compounds with a chiral auxiliary in a solvent to precipitate a partial stereoisomer salt of the compound and chiral auxiliary in excess of a mirror image. It may relate to a chiral resolution method of a stereoisomer mixture.

In one aspect of the invention, the chiral auxiliary is 2,3-dibenzoyl tartaric acid, O, O'-di-p-toluoil. It may be one or more selected from the group consisting of tartaric acid), their stereoisomers, and combinations thereof.

As used herein, the term "in excess of enantiomer" generally includes all increases in the proportion of enantiomers, and thus not only the excess of enantiomer compared to the racemic mixture, but also the ratio of enantiomers is 1. Means an increase in one enantiomer compared to other mixtures that are not: 1 (same as racemic). In one aspect of the present invention, the term "in excess of mirror image" means that the excess amount of mirror image (% ee) is 80% or more, 82% or more, 84% or more, 86% or more, 88% or more, 90% or more, 92%. As mentioned above, it may mean those corresponding to 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more. Similarly, the term "high optical purity" herein corresponds to a term well known in the art of the present invention. In one aspect of the present invention, the term "high optical purity" is 80% or more, 82% or more, 84% or more, 86% or more, 88% or more, 90% or more, 92% or more, 94% or more, 95% or more. , 96% or more, 97% or more, 98% or more, or 99% or more of the mirror image excess amount (% ee).

In the present specification, the chiral auxiliary is something that can be self-recognized by ordinary engineers belonging to the technical field of the present invention, and specifically, it regulates the stereochemical result of the synthesis in the synthesis of an organic compound. It may mean a compound that is temporarily integrated during its synthesis to make such a chiral auxiliary an auxiliary to determine the stereoselectiveness of one or more series of reactions. (See Wikipedia's chiral auxiliary page (http://en.wikipedia.org/wiki/Chiral_auxiliary)). Chiral auxiliary and chiral acid may be used interchangeably herein.

In one aspect of the invention, 2,3-dibenzoyl-tartaric acid is either (+)-2,3-dibenzoyl-D-tartaric acid or (-)-2,3-dibenzoyl-L-tartaric acid, which are optical isomers of each other. Also, O, O'-di-p-tartaric acid is an optical isomer of each other (+)-O, O'-di-p-tartaric acid-D-tartaric acid or (-)-O, It may be O'-di-p-toroil-L-tartaric acid. In the case of such a tartaric acid derivative, D-type and L-type can be used individually or in combination, but it is preferable to use them without mixing with each other. When the optical isomers D-type and L-type of the tartaric acid derivative are combined and used in the method according to one aspect of the present invention, the optical purity value is lower than when the D-type or L-type is used, respectively.

In one aspect of the invention, the stereoisomeric mixture may be a stereoisomeric mixture of compounds having an asymmetric carbon atom. Specifically, in one aspect of the present invention, the compound having an asymmetric carbon atom may be one to which an amine group is bonded. Specifically, in one aspect of the invention, the compound may have a substituted or unsubstituted phenyl group attached to an asymmetric carbon atom in addition to the amine group. Specifically, in one aspect of the present invention, the compound having an asymmetric carbon atom may be a compound having a structure represented by the following chemical formula 1.

In one aspect of the present invention, the method may be a method of obtaining an R-type or S-type optical isomer having high optical purity from a mixture of stereoisomers.

In one aspect of the invention, the method comprises (+) -2,3-dibenzoyl-D-tartaric acid, (+)-O, O'-di-p-toroil-D-tartaric acid, and their chiral auxiliary. When it is one selected from the group consisting of the combination of the above, it may be a method of obtaining the S-type optical isomer of the compound in a high amount of excess mirror image.

In one aspect of the invention, the method comprises (-)-2,3-dibenzoyl-L-tartaric acid, (-)-O, O'-di-p-toroil-L-tartaric acid, and their chiral auxiliary. When it is one selected from the group consisting of the combination of the above, it may be a method of obtaining the R-type optical isomer of the compound in a high amount of excess mirror image.

In one aspect of the present invention, the compound may have a structure represented by the following chemical formula 1.

The R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are H; -NH ₂ ; an alkyl group of _{C 1-6} ; an alkenyl _{group of C 2-6; C.} It is one selected from the group consisting of _{2-6 alkynyl groups; and halogens, and R 1} and R ₂ have different substituents from each other.

In one aspect of the invention, the halogen may be one or more selected from the group consisting of F, Cl, Br, and I.

In one aspect of the present invention, R ₁ is one selected from the group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group, and R ₂ may be hydrogen.

In one aspect of the invention, R ₁ is a methyl group, R ₃ and R ₇ are hydrogen, and R ₄ , R ₅ , and R ₆ are F, Cl, Br, I, and C _1-6 . It may be one selected from the group consisting of alkyl groups.

In one aspect of the invention, R ₄ and R ₆ may be F and R ₅ may be a methyl group.

In one aspect of the invention, the compound may be N- {4-[(1R / S) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide.

In one aspect of the invention, the solvent may be a polar aprotic solvent.

In one aspect of the invention, the polar aprotic solvent may be one or more selected from the group consisting of ethyl acetate, tetrahydrofuran, acetonitrile, acetone, and combinations thereof. Specifically, the polar aprotic solvent may be acetone.

In one aspect of the invention, the solvent may be added in an amount that dissolves all the mixtures. Specifically, in one aspect of the invention, the solvent may be in multiples of 2-80 with respect to the total weight of the stereoisomer mixture, specifically in multiples of 5-30, more specifically in 5-. It may be a multiple of 15, or more specifically, a multiple of 10 (ie, volume (solvent) / mass (stereoisomer, or (v / w)). In one aspect, the solvent is the total of the stereoisomer mixture. 2x or more, 5x or more, 10x or more, 20x or more, 30x or more, 40x or more, 50x or more, 60x or more, 70x or more, or 80x or more and 80x or more with respect to the weight Below, it may be 70 times or less, 60 times or less, 50 times or less, 40 times or less, 30 times or less, 20 times or less, 15 times or less, 10 times or less, or 5 times or less.

In one aspect of the invention, in the method the mixing may be carried out by increasing the temperature of the mixture to 40 ° C. to 70 ° C., the boiling point of the solvent, or the boiling point of the solvent mixture.

In one aspect of the invention, the mixing may be to increase the temperature with stirring for 1 to 4 hours.

In one aspect of the present invention, the stirring may be reflux stirring.

In one aspect of the present invention, the temperature is 30 ° C. or higher, 40 ° C. or higher, 50 ° C. or higher, 60 ° C. or higher, or 70 ° C. or higher, and 70 ° C. or lower, 60 ° C. or lower, 50 ° C. or lower, 40 ° C. or lower. , Or 30 ° C. or lower. Specifically, the temperature may be 40 ° C. or higher and 60 ° C. or lower, more specifically, 45 ° C. or higher and 55 ° C. or lower, and more specifically, 50 ° C. or lower.

In one aspect of the present invention, the stirring time is 1 hour or more, 2 hours or more, 3 hours or more, 4 hours or more, or 5 hours or more, and 6 hours or less, 5 hours or less, 4 hours or less, 3 hours. Below, it may be 2 hours or less, or 1 hour or less. Specifically, the stirring time may be 2 hours or more and 4 hours or less, and more specifically, the stirring time may be 2 hours 30 minutes to 3 hours 30 minutes, and more specifically, the stirring time may be 2 hours 30 minutes to 3 hours 30 minutes. It may be 3 hours.

In one aspect of the invention, the equivalent ratio of the chiral auxiliary to 1 molar equivalent of the stereoisomer mixture may be 0.5 to 2.0 equivalents, more specifically 0.8 to 1.5 equivalents. ..

In one aspect of the present invention, the equivalent ratio of the chiral auxiliary to 1 molar equivalent of the steric isomer mixture is 0.10 equivalent or more, 0.2 equivalent or more, 0.3 equivalent or more, 0.4 equivalent or more. 0.5 equivalents or more, 0.6 equivalents or more, 0.7 equivalents or more, 0.8 equivalents or more, 0.85 equivalents or more, 0.90 equivalents or more, 0.95 equivalents or more, 1.0 equivalents or more 1. 05 equivalents or more, 1.1 equivalents or more, 1.15 equivalents or more, 1.2 equivalents or more, 1.3 equivalents or more, 1.4 equivalents or more, 1.5 equivalents or more, or 2.0 equivalents or more, and 2.0 equivalents or less, 1.5 equivalents or less, 1.4 equivalents or less, 1.3 equivalents or less, 1.2 equivalents or less, 1.14 equivalents or less, 1.1 equivalents or less, 1.05 equivalents or less 1. 0 equivalents or less, 0.95 equivalents or less, 0.90 equivalents or less, 0.85 equivalents or less, 0.8 equivalents or less, 0.7 equivalents or less, 0.6 equivalents or less, 0.5 equivalents or less, 0.4 equivalents Hereinafter, it may be 0.3 equivalents or less, 0.2 equivalents or less, or 0.10 equivalents or less.

In one aspect of the invention, the stereoisomer mixture may have an R-type: S-type isomer ratio of 1: 9 to 9: 1, all between 1: 9 and 9: 1. It may be an integer ratio. Specifically, in one aspect of the present invention, the stereoisomer mixture has a ratio of R-type isomer: S-type isomer of 1: 9 or less, 1: 8 or less, 1: 7 or less, 1: 6 or less. 1: 5 or less, 1: 4 or less, 1: 3 or less, 1: 2 or less, or 1: 1 or less, and 1: 1 or more, 1: 2 or more, 1: 3 or more, 1: 4 or more, 1 : 5 or more, 1: 6 or more, 1: 7 or more, 1: 8 or more, or 1: 9 or more.

In one aspect of the invention, the method comprises precipitating a partial stereoisomer salt of a compound having a structure represented by Chemical Formula 1 and a chiral auxiliary in excess of a mirror image, followed by the precipitated partial stereoisomer salt. It may further include a step of collecting and adjusting the ratio of R-type isomer: S-type isomer of the stereoisomer mixture contained in the mother liquor to 3: 7 to 7: 3. Specifically, in one aspect of the present invention, the step of adjusting the ratio of R-type isomer: S-type isomer changes the ratio from 3: 7 to 7: 3, 4: 6 to 6: 4, 7: 8. It may be adjusted to ~ 8: 7, 9: 11-11: 9, 12:13 to 13:12, or it may be adjusted to a ratio of about 5: 5.

In one aspect, the present invention obtains 80% ee or more, 82% ee or more, 84% ee or more, 86% ee or more, 88% obtained by dividing from a stereoisomer mixture by the method according to one aspect of the present invention. Concerning stereoisomers of compounds having a mirror image excess amount of ee or more, 90% ee or more, 92% ee or more, 94% ee or more, 96% ee or more, 97% ee or more, 98% ee or more, or 99% ee or more. It may be a thing.

In one aspect of the invention, the stereoisomers are N- {4-[(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide or N- {4-[(1S) -1. It may be −aminoethyl] -2,6-difluorophenyl} methanesulfonamide.

In one aspect of the invention, an asymmetric carbon atom means carbon when the carbon atoms in the molecule are attached to four different atoms, atomic groups, or functional groups. Compounds containing such an asymmetric carbon atom have optical activity, optical activity, or optical isomers.

In one aspect of the invention, the stereoisomeric mixture may mean a mixture of two enantiomers as optically active isomer compounds, at a mixing ratio of 1: 1. It may be (in such a case, a racemic mixture), or the mixing ratio may correspond to an integer ratio between 1:10 to 10: 1. In one aspect of the present invention, the stereoisomer mixture may be an artificially synthesized mixture or a mixture in which the ratio of the R-type optical isomer and the S-type optical isomer is unknown. According to the method of the present invention, the ratio of either the R-type or S-type optical isomer can be significantly increased, so that the optical isomer of the desired form can be highly optical regardless of the ratio of the mixture. It can be obtained with purity.

In one aspect of the invention, N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide is a compound of CAS No. 1202743-51-8 with a molecular weight of 250.27 Da. Means the applicable one and may be used interchangeably with INT-2 herein, which may be a mixture of stereoisomers mixed with R or S type optical isomers.

In one aspect of the present invention, N- {4-[(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide hydrochloride corresponds to CAS No. 956901-23-8. The molecular weight corresponds to 286.73 Da, and its component N- {4-[(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide is assigned to CAS No. 957103-01-4. Means the applicable one. In addition, it may be used interchangeably with the R-type isomer of INT-3 in the present specification.

In one aspect of the present invention, 3- (2-propyl-6-trifluoromethyl-pyridine-3-yl) -acrylic acid corresponds to CAS No. 1005174-17-3 and has a molecular weight of 259.22 Da. Means the one that corresponds to.

In one aspect of the invention, (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridine- 3-Il) -acrylamide (PAC-14028) means that it corresponds to CAS No. 100518-10-4 and corresponds to a molecular weight of 491.47 Da.

In one aspect of the invention, the R-type or S-type optical isomers of INT-3 may be obtained according to the following methods:
The step of mixing INT-2 (N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide) with a chiral auxiliary;
The step of adding a polar aprotic solvent in multiples (v / w) of the weight of INT-2 to the mixture;
The step of refluxing and stirring the mixed solution to which the polar aprotic solvent is added at 30 ° C. to 70 ° C. over 1 hour to 4 hours;
The step of cooling the agitated mixture;
A method comprising the step of filtering a solid produced by cooling to obtain INT-3 chiralate.

In one aspect of the present invention, the cooling may be cooling to a temperature of 15 ° C. to 30 ° C. after reflux.

In one aspect of the present invention, cooling is 10 ° C. or higher, 15 ° C. or higher, 20 ° C. or higher, 22 ° C. or higher, 24 ° C. or higher, 25 ° C. or higher, 26 ° C. or higher, 28 ° C. or higher, 30 ° C. or higher, or 35 ° C. or higher. And 40 ° C or lower, 35 ° C or lower, 30 ° C or lower, 28 ° C or lower, 26 ° C or lower, 25 ° C or lower, 24 ° C or lower, 22 ° C or lower, 20 ° C or lower, 15 ° C or lower, 10 ° C or lower, or 5 It may be cooled to a temperature of ° C. or lower.

In one aspect of the invention, the method may further comprise a step of separating the chiral acid from the obtained INT-3 chiralate, specifically the separation step to the INT-3 chiralate. After adding 5 times the weight ratio of water and 2 equivalents of a 28% by volume aqueous ammonia solution, the suspension obtained by stirring for 20 to 50 minutes is filtered, and excess water is removed by vacuum vacuum to remove excess water, and INT- It may obtain 3 R-type or S-type optical isomers.

The present invention may, in one aspect, relate to a chiral division method of a stereoisomer mixture comprising the following steps:
(1) A step of mixing a stereoisomer mixture of a compound in which an amine group is bonded to an asymmetric carbon atom with a chiral auxiliary.

In one aspect of the invention, the compound may be N- {4-[(1R / S) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide.

In one aspect of the invention, the chiral auxiliary in step (1) consists of 2,3-dibenzoyl-tartaric acid, O, O'-di-p-toluoil tartaric acid, their stereoisomers, and combinations thereof. It may be one or more selected from the group.

In one aspect of the invention, the method may further include after step (1), step (2) adding a solvent to the mixture of steps (1).

In one aspect of the invention, the solvent may be a polar aprotic solvent.

In one aspect of the invention, the method may further include (3) reflux stirring the mixed solution to which the solvent has been added.

In one aspect of the present invention, the stirring in step (3) is 30 minutes or more, 1 hour or more, 1 hour 30 minutes or more, 2 hours or more, 2 hours 30 minutes or more, 3 hours or more, 3 hours 30 minutes or more, or Stir for 4 hours or more, and 5 hours or less, 4 hours 30 minutes or less, 4 hours or less, 3 hours 30 minutes or less, 3 hours or less, 3 hours 30 minutes or less, 3 hours or less, 2 hours 30 minutes or less, 2 hours Hereinafter, stirring may be performed for 1 hour and 30 minutes or less, 1 hour or less, or 30 minutes or less.

In one aspect of the present invention, the stirring in step (3) is 20 ° C. or higher, 25 ° C. or higher, 30 ° C. or higher, 35 ° C. or higher, 40 ° C. or higher, 45 ° C. or higher, 50 ° C. or higher, 55 ° C. or higher, or 60 ° C. Stir at the above temperature and 70 ° C or lower, 65 ° C or lower, 60 ° C or lower, 55 ° C or lower, 50 ° C or lower, 45 ° C or lower, 40 ° C or lower, 35 ° C or lower, 30 ° C or lower, 25 ° C or lower, or Stirring may be performed at a temperature of 20 ° C. or lower.

In one aspect of the invention, the method may further comprise the step of cooling the mixture in steps (4) and (3).

In one aspect of the invention, the method may further comprise (5) filtering the solid produced by cooling to obtain a partial stereoisomer salt of the compound. Specifically, in one aspect of the present invention, the partial stereoisomer salt of the compound may be an INT-3 partial stereoisomer salt.

In one aspect of the invention, the method may further comprise (6) the step of removing or separating chiral acid from the obtained partial stereoisomer salt.

In one aspect of the present invention, the step (6) may include 1) adding water and an aqueous ammonia solution to the partial stereoisomer salt of INT-3. Specifically, in one aspect of the present invention, in step (6), water is at least two times, three times or more, four times or more, five times or more, six times or more the weight ratio of the INT-3 partial steric isomer salt. , Or 7 times or more, and may be 7 times or less, 6 times or less, 5 times or less, 4 times or less, 3 times or less, or 2 times or less. Specifically, in one aspect of the present invention, in step (6), the aqueous ammonia solution is 20% by volume or more, 24% by volume or more, 28% by volume or more, 32% by volume or more, 36% by volume or more, or 40% by volume or more. It may be an aqueous ammonia solution of 40% by volume or less, 36% by volume or less, 32% by volume or less, 28% by volume or less, 24% by volume or less, or 20% by volume or less. Specifically, in one aspect of the present invention, in step (6), the aqueous ammonia solution is 0.5 equivalents or more, 1 equivalent or more, 1.5 equivalents or more, 2 equivalents or more, 2.5 equivalents or more, or 3 equivalents or more. It may be charged 4 equivalents or less, 3.5 equivalents or less, 3 equivalents or less, 2.5 equivalents or less, 2 equivalents or less, 1.5 equivalents or less, 1 equivalent or less, or 0.5 equivalents or less. ..

In one aspect of the present invention, the step (6) may further include a step of stirring the mixture after 2) step 1). Specifically, in one aspect of the present invention, in the step (6), stirring is performed for 5 minutes or more, 10 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, 50 minutes or more, 60 minutes or more, or 70. It may be stirred for 70 minutes or less, 60 minutes or less, 50 minutes or less, 40 minutes or less, 30 minutes or less, 20 minutes or less, or 10 minutes or less.

In one aspect of the invention, step (6) may further include 3) filtering the suspension obtained by stirring.

In one aspect of the invention, step (6) further comprises 4) removing water from the filtered suspension under reduced pressure vacuum to obtain the R-type or S-type optical isomer of INT-3. You can stay.

In one aspect, the present invention is a step of chirally dividing a stereoisomer mixture of a compound having the structure represented by the above chemical formula 1 by the method according to one aspect of the present invention; and the divided stereoisomers being divided into the chemical formula 3a or Including the step of converting to a compound having the structure shown in 3b.

The R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are H; -NH ₂ ; an alkyl group of _{C 1-6} ; an alkenyl _{group of C 2-6; C.} One selected from the group consisting of _{2-6 alkynyl groups; and halogens.}
The R ₁ and R ₂ may relate to a method for producing a compound having a structure represented by the chemical formula 3a or 3b having different substituents. The conversion step is also specifically described in Korean Patent Application No. 10-2009-7004333.

In one aspect of the present invention, the compound having the structure represented by the chemical formula 3a is (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- ( The compound which is 2-propyl-6-trifluoromethyl-pyridine-3-yl) -acrylamide (PAC-14028) and has the structure represented by the above chemical formula 1 is N- {4-[(1R / S)-. It may be 1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide.

In one aspect of the invention, the step of converting the split stereoisomer into a compound having the structure represented by Chemical Formula 3a or 3b is N- {4-[(1R) -1-aminoethyl] -2,. Including the step of coupling 6-difluorophenyl} methanesulfonamide (INT-3) with 3- (2-propyl-6-trifluoromethyl-pyridine-3-yl) -acrylic acid (INT-7). It may be there.

The stereoisomers divided by the method according to one aspect of the present invention are used in reacting with the substance described in Korean Patent Application No. 10-2009-700433 to produce a novel drug described in the application. It may be used as an intermediate. Therefore, in one aspect, the present invention is a method for producing a novel drug described in Korean Patent Application No. 10-2009-700433 using a stereoisomer divided by the method according to one aspect of the present invention. It may relate to a novel drug produced by this method.

In one aspect, the present invention has 96% or more, 97% or more, 98% or more, or 99% or more mirror excess amounts produced by the method according to one aspect of the present invention (R) -N- [1. -(3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridine-3-yl) -acrylamide may be relevant.

The present invention, in one aspect, was produced by the method according to one aspect of the present invention (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3-. It may relate to a TRPV1 antagonist containing (2-propyl-6-trifluoromethyl-pyridine-3-yl) -acrylamide (PAC-14028) as an active ingredient. Such a TRPV1 antagonist may be used as a pharmaceutical composition for the prevention or treatment of the following diseases.

In one aspect, the present invention relates to (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-) according to one aspect of the present invention. Pain, inflammatory diseases of the joints, including 6-trifluoromethyl-pyridine-3-yl) -acrylamide, its optical isomers, or its pharmaceutically acceptable salts and pharmaceutically acceptable carriers. Neuropathy, HIV-related neuropathy, neuropathy, neuropathy, stroke, urinary incontinence, cystitis, gastroduodenal ulcer, irritable colon syndrome (IBS) and inflammatory bowel disease (IBD), urgency stool incontinence, gastroesophageal tract Reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, nervous / allergic / inflammatory skin disease, psoriasis, pruritus, itch, skin irritation, eye or mucosal inflammation, hyperacusis , Ear ringing, vestibular hypersensitivity, paroxysmal dizziness, myocardial ischemia, hirsutism, hair loss, alopecia, rhinitis, and pancreatitis associated with pathological irritation and / or abnormal development of vanilloid receptors selected from the group It may relate to a pharmaceutical composition for the prevention or treatment of the disease.

In one aspect of the invention, the pain includes osteoarthritis, rheumatoid arthritis, tonic spondylitis, diabetic neuropathy pain, postoperative pain, toothache, fibrotitis, myocardial pain syndrome, lower back pain, migraine, and others. It may be a disease selected from the group consisting of the types of headaches, or it may be pain associated with the disease.

The present invention may, in one aspect, relate to an optical resolution kit comprising a chiral auxiliary; a polar aprotic solvent; and instructions for use of the chiral auxiliary.

In one aspect of the invention, the chiral auxiliary was selected from the group consisting of 2,3-dibenzoyl tartaric acid, O, O'-di-p-toluoil-tartaric acid, their stereoisomers, and combinations thereof. It may be one or more.

In one aspect of the invention, the chiral auxiliary may be 0.5 to 2.0 equivalents relative to 1 molar equivalent of the stereoisomer mixture to be optically resolved.

In one aspect of the invention, the salt forming aid compound may be 0.8 to 1.5 equivalents relative to 1 molar equivalent of the stereoisomer mixture to be optically resolved.

In one aspect of the invention, the instructions for use describe 0.5 to 2.0 equivalents of the chiral auxiliary to 1 molar equivalent of the stereoisomer mixture to be optically resolved when using the optical resolution agent. Therefore, it may include the content that it must be used in an amount of 0.8 to 1.5 equivalents.

In one aspect of the invention, the instructions for use may include mixing with a stereoisomer mixture under a polar aprotic solvent when using a chiral auxiliary.

In one aspect of the present invention, the instruction manual may describe the content relating to the chiral division method of the stereoisomer mixture according to one aspect of the present invention.

Hereinafter, the present invention will be described based on the following examples and test examples. Examples and Test Examples are for explaining the present invention in more detail, and the scope of the present invention is not limited to the scope of the following Examples. In addition, it is clear that anyone with ordinary knowledge in this technical field can make various modifications and imitations within the scope of the appended claims without departing from the scope of the technical idea of the present invention. It is a fact.

[Comparative Test Example 1] Measurement of Optical Purity by Conventional Asymmetric Synthesis Method The conventional asymmetric synthesis method was carried out as shown in Reaction Scheme 1 below.

N- {2,6-difluoro-4- [1- (2-methyl-propan-2-sulfinylimino) -ethyl] -phenyl} -methanesulfonamide (1 equivalent) corresponds to 10 times its weight. It was added to tetrahydrofuran (tetrahydrofuran, THF) (20 ml) to dissolve it, and NaBH ₄ (4 equivalents) was further dissolved in the solution, and then the reaction was carried out at the temperature shown in Table 1 below for 10 hours. After that, CH ₃ OH was added dropwise until no more hydrogen gas was released.

The mixture is concentrated under reduced pressure and then purified by chromatography to purify N- {2,6-difluoro-4- [1- (2-methyl-propan-2-sulfinylamino) -ethyl] -phenyl}-. A methanesulfonamide was obtained. 4M HCl in dioxane was overdose and the mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The preparation residue was recrystallized from acetone and purified to obtain (R) -N- [4- (1-amino-ethyl) -2,6-difluoro-phenyl] -methanesulfonamide, an HCl salt. ..

The salt thus obtained was subjected to the same steps as the method of the following test example to measure the excess amount of the mirror image, and the results are shown in Table 1 below.

According to the conventional method, in order to obtain an optical activity of 96% or more, it is necessary to maintain a temperature of −40 ° C. or lower continuously for 10 hours as shown in Table 1, according to the present invention. For example, the same optical activity can be achieved only by stirring at a temperature of 50 ° C. and purifying with a solvent. Therefore, it can be determined that the method of the present invention is significantly more economical than the conventional method. Also, when such a reaction is scaled up on a factory-by-factory basis, it is much easier to maintain a temperature of 50 ° C than to maintain a temperature of -40 ° C for 10 hours, resulting in this. The method of the present invention has the effect that the scale of the reaction can be expanded more easily than the conventional method.

Further, in the case of the conventional method, since 2 to 4 equivalents of sodium borohydride are used, explosive hydrogen is excessively generated and heat is generated in the reaction termination process, which is extremely difficult. Corresponds to a process involving a dangerous reaction. On the other hand, the present invention obtains a commercially available stereoisomer having optical activity without dangerous steps such as excessive generation of explosive hydrogen or generation of heat. It has the characteristic of producing a heterogeneous effect of being able to do it.

Therefore, according to such a result, the present invention corresponds to a method involving a step that is more economical and secures safety as compared with the conventional method.

[Comparative Test Example 2] Measurement of separation form and optical purity when separated using a polar protonic solvent According to the production method described in Bioorganic & Medicinal Chemistry (15 (18), 6043-6053; 2007). N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide (a mixture of R and S-type isomers, R: S = 1: 1) was produced. The N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide thus produced and the optical resolution agent shown in Table 2 below (purchased from Sigma-Aldrich) were used, respectively. 1 equivalent was mixed. Solvents that are 10 times the weight of N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide in the mixture thus mixed (different polarities according to Table 2 below). Protic solvent) was added. The mixed solution to which the solvent was added was refluxed at 50 ° C. for 3 hours and then cooled to 25 ° C. The resulting solid was filtered through a Büchner funnel to obtain the respective N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide chiralate.

Each N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide chiralate thus obtained is mixed with water in a weight ratio of 5 times and 2 equivalents of a 28% by volume ammonia aqueous solution. The suspension obtained by stirring for 30 minutes was filtered through a Buchner funnel, excess water was removed in a vacuum under reduced pressure, and each N- [4-[(1R) -1-aminoethyl]- 2,6-Difluorophenyl] -methanesulfonamide or N- [4-[(1S) -1-aminoethyl] -2,6-difluorophenyl] -methanesulfonamide was obtained.

For the INT-3 thus obtained, the optical purity (mirror image excess amount) was analyzed with a chiral HPLC column (Shiseido Chiral CD-Ph 4.6 mm × 250 mm, 5 μm). A mixture of 0.5 mol / L sodium perchlorate and methanol (75% by volume: 25% by volume) was used as the mobile phase, and the ratio of each chiralate separated into a solid under the following conditions was determined by Waters e2695 Alliance HPLC. It was measured using it. Using the mathematical formula 1 based on the ratio of each salt, the optical purity (Enantiomeric excess, ee%) of each salt can be calculated.

The measurement results for the ratio of each salt are shown in Table 2 below.

<HPLC conditions>
1. 1. Column temperature = 35 ° C
2. Flow velocity = 0.5 ml / min 3. Detection = 220 nm
4. Rt (min) = 20.4 (R-enantiomer%), 18.9 (S-enantiomer%)

Based on these results, it can be confirmed that, unlike the method according to the present invention, when a polar protic solvent is used, the R-type isomer can be separated and obtained using a D-type chiral auxiliary. Further, when a solvent in which isopropyl alcohol, which is a polar protic and aprotic solvent, and acetone, which is a polar aprotic solvent, are mixed at a ratio of 1: 1 is used, R-type isomers and S-type isomers are obtained in the same ratio. It was confirmed that when solvents having different properties are mixed and used in this way, the steric isomer mixture is not separated.

[Test Example 1] Confirmation of feasibility of separation when separated using a polar aprotic solvent The method described in Comparative Test Example 2 is followed, but the solvent is not a polar protic solvent, as shown in Table 3 below. Experiments were carried out using polar aprotic solvents. When such an experiment was carried out, the ratio of each isomer separated into a solid was measured under the HPLC conditions of Comparative Test Example 2, and the results are shown in Table 3.

According to the above results, when the D-type chiral auxiliary is reacted with the stereoisomer mixture in a polar aprotic solvent by the method according to one aspect of the present invention, the S-type stereo in most polar aprotic solvents. It was confirmed that the isomers were obtained at a higher ratio. In the case of dimethylformamide and dimethyl sulfoxide, N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide chiralate exists in a state where it is completely dissolved in a solvent and is not separated into a solid. Therefore, it was not possible to determine the presence or absence of the separation.

The equivalent of the chiral auxiliary was adjusted as follows with respect to acetone, which was able to obtain the S-type isomer in the highest ratio in such a polar aprotonic solvent, and the R-type isomer was adjusted in the stereoisomer mixture. The ratio of the isomer to the S-type isomer was adjusted, and the ratio and yield of the obtained isomer compound were measured.

[Test Example 2] Measurement of ratio and yield by equivalent of chiral auxiliary using acetone solvent The experiment is carried out according to the method described in Comparative Test Example 2, but acetone is used as a solvent and the equivalent of chiral auxiliary is measured. The experiments were carried out differently from each other as shown in Table 4 below. The ratio of each isomer separated into the solid was measured under the HPLC conditions of Comparative Test Example 2, and the reaction yield was calculated by the following mathematical formula 2. The results are shown in Table 4.

From the above results, it was confirmed that the ratio and yield of the isomers obtained in the solid changed depending on the equivalent of the stereoisomer mixture and the chiral auxiliary. When the equivalent of the chiral auxiliary to 1 equivalent of the stereoisomer mixture is 1 equivalent or more, the S-type isomer is separated, and the ratio of the S-type isomer is when the equivalent of the chiral auxiliary is 1.2 equivalent. It was the highest. Furthermore, the yield when the S-type isomer was separated was also the highest when the equivalent of the chiral auxiliary was 1.2 equivalents.

[Test Example 3] Measurement of optical purity and yield by R: S ratio of stereoisomer mixture and equivalent of chiral auxiliary The experiment is carried out according to the method described in Comparative Experimental Example 2, but N- [4- ( Experiments were performed with a ratio of R and S-type isomers of 14:86 in 1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide, and the equivalents of the chiral auxiliary are shown in Table 5. The experiment was carried out differently from each other. The ratio of each isomer separated into the solid was measured under the HPLC conditions of Comparative Test Example 2, and the reaction yield was calculated by the above mathematical formula 2.

In addition, N- [4-[(1R) -1-aminoethyl] -2,6-difluorophenyl] -methanesulfonamide or N- [4-[(1S) -1-aminoethyl] -2 of each solid After obtaining the 6,6-difluorophenyl] -methanesulfonamide, the ratio of the S-type isomer and the R-type isomer contained in the mother liquid was measured under the HPLC conditions of Comparative Test Example 2. The results are shown in Table 5 below.

When the L-type chiral auxiliary is used in Tables 5 to 7, the ratios of the R-type isomer and the S-type isomer are obtained in opposite directions.

According to the results in Table 5, when the ratio of R-type isomer: S-type isomer of the stereoisomer mixture is 14:86, the ratio of S-type isomer is higher than that in Table 4. I was able to get it.

When the amount of chiral auxiliary was 1 equivalent or more with respect to 1 equivalent of the steric isomer mixture, the S-type isomer compound was obtained in a higher ratio than that of the steric isomer mixture before the reaction. In particular, when the chiral auxiliary was 1.0 equivalent, the ratio of the S-type isomer separated into the solid was 97% and the yield was 74%, and the highest result could be obtained.

In particular, when the chiral auxiliary is 1.0 equivalent, in the isomer mixture remaining in the reaction mother liquor after obtaining the S-type isomer compound precipitated as a solid, the R-type isomer: S-type isomer The ratio was adjusted to 45:55. This indicates that almost only the S type is selectively separated.

Further, in the stereoisomer mixture, even in the case of Table 6 in which the ratio of R-type isomer: S-type isomer is 25:75 and in the case of Table 7 in which the ratio is 10:90, the results are higher than those in Table 4. The S-type isomer compound could be obtained at a high ratio.

Specifically, when the amount of chiral auxiliary was 1 equivalent or more with respect to 1 equivalent of the stereoisomer mixture, the S-type isomer compound was obtained in a higher ratio than that of the stereoisomer mixture before the reaction. In particular, when the chiral auxiliary is 1.0 equivalent, the proportions of the S-type isomers separated into solids are 88% and 98%, respectively, and the yields are 72% and 76%, respectively, which are the highest. I was able to get the result. Further, as can be seen from the results in Table 6, when the R: S ratio is 25:75 and the chiral auxiliary is 1.2 equivalents, the isomer compound remains in the mother liquor after being separated into a solid. It can be confirmed that the ratio of R: S is adjusted to 51:49.

Therefore, according to the method according to one aspect of the present invention, it is possible to selectively separate only the S-type isomer compound from the stereoisomer mixture having a higher S-type ratio at a high ratio. After the separation method is carried out, the ratio of the R-type isomer and the S-type isomer contained in the mother liquor remains close to 1: 1. Therefore, only the S-type isomer is removed to form a stereoisomer mixture. Can be separated into racemates.

Further, the separated S-type isomer compound having high optical purity can obtain the racemate of the three-dimensional isomer compound by another racemization step.

Therefore, in the method according to one aspect of the present invention, racemization can be carried out using a mixture of three isomers while minimizing the loss of the R-type isomer, and the racemate thus obtained can be used. It has the advantage that it can be used for another reaction again.

Further, the method according to one aspect of the present invention can minimize the loss of the R-type isomer due to the racemization process, and can racemize only the selectively separated S-type to racemize from the S-type. Therefore, according to the method according to one aspect of the present invention, the S-isomer can be separated from the stereoisomer mixture in a high yield under a polar aprotic solvent, and the mother liquor is used again in the chiral division method. It is possible to produce similar to racemic so that it can be produced.

Further, according to the method according to one aspect of the present invention, a solid obtained by obtaining an R-type isomer compound using a polar protonic solvent and a D-type chiral auxiliary, and then crystallizing the remaining mother liquor with an aqueous ammonia solution. By treating the compound (R: S = 14: 86) with the same D-type chiral auxiliary and simply changing to a polar aproton solvent, the S-type isomer compound is selectively separated and the mother liquor is reconstituted. It can be produced at a ratio similar to that of the racemate (R: S is close to 1: 1) so that it can be used in the chiral division reaction, and the separated S-type is racemicized to form a racemic compound (R). : S = 1: 1) can be produced. This is a method that minimizes the desired R-type loss and enables the production of a racemic compound. Therefore, it can be said that the method according to one aspect of the present invention is advantageous for process application because it uses the same type of chiral auxiliary as the step of separating R-type isomers and there is no cross-contamination by contradictory chiral auxiliary. .. Therefore, the R-type isomer is obtained by a method of changing only the solvent, and the mother liquor containing the stereoisomer mixture that has undergone the chiral division method can be continuously recycled, and is easily racemicized and put into the chiral division method again. It has the effect of being extremely economical and environmentally friendly in that it can be used.

When the L-type chiral auxiliary is used in the method according to one aspect of the present invention and the above experiment, an R-type stereoisomer compound can be obtained, and such an R-type isomer compound corresponds to INT-3. And can be used in additional steps as described below.

[Test Example 4]
(R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridine-3-yl) -acrylamide Manufacturing

Using N- {4-[(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide produced according to one aspect of the present invention, (R) -N- [1-( 3,5-Difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridine-3-yl) -acrylamide, Korean Patent Application No. 10-2009-7004333 Manufactured according to the method described in.

Specifically, N- {4-[(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide, HCl salt (62 mg, 0.22 mmol) was added to 3- (2-propyl-6-). The title compound (81 mg, 73%) was obtained by reacting with trifluoromethyl-pyridine-3-yl) -acrylic acid (56 mg, 0.22 mmol) to crystallize into ether and purifying.

¹ H NMR (300MHz, DMSO-d ₆ ): δ 9.50 (bs, 1H), 8.81 (d, 1H, J = 7.8Hz), 8.16 (d, 1H, J = 8.4Hz), 7.80 (d, 1H, J = 7.8Hz), 7.67 (d, 1H, J = 15.6Hz), 7.18 (d, 2H, J = 7.2Hz), 6.76 (d, 1H, J = 15.6Hz), 5.04 (m, 1H), 3.05 (s, 3H), 2.91 (m, 2H), 1.65 (m, 2H), 1.41 (d, 3H, J = 6.9Hz), 0.92 (t, 3H, J = 7.2Hz).
ESI [M + H] ⁺ : 492

Therefore, the R-type isomer of the compound having the structure represented by Chemical Formula 1 divided by one aspect of the present invention can act as a TRPV1 antagonist by the substance or method described in Korean Patent Application No. 10-2009-7004333. It can be effectively used as an intermediate necessary for producing various novel compounds.

Claims (20)

A chiral resolution method for a mixture of steric isomers.
A stereoisomer mixture of the compound having the structure represented by the following chemical formula 1 is mixed with a chiral auxiliary under a polar aproton solvent, and the compound having the structure represented by the chemical formula 1 and the chiral auxiliary are mixed. Including the step of precipitating a partial stereoisomer salt in excess of the mirror image.

The stereoisomer mixture has an R-type isomer: S-type isomer ratio of 1: 9 to 9: 1.
In the method, after the step of precipitating the compound having the structure represented by the chemical formula 1 and the partial stereoisomer salt of the chiral auxiliary in an excess amount of the mirror image, the precipitated partial stereoisomer salt is recovered and contained in the mother liquor. Further including the step of adjusting the ratio of the R-type: S-type isomer of the obtained stereoisomer mixture to 3: 7 to 7: 3.
The R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are H; -NH ₂ ; an alkyl group of _{C 1-6} ; an alkenyl _{group of C 2-6; C.} One selected from the group consisting of _{2-6 alkynyl groups; and halogens.}
The R ₁ and R ₂ have different substituents from each other.
A chiral resolution method for a mixture of steric isomers. The R ₂ is hydrogen and the chiral auxiliary is selected from the group consisting of 2,3-dibenzoyl tartaric acid, O, O'-di-p-toluoil-tartaric acid, their stereoisomers, and combinations thereof. The method according to claim 1, wherein the method is one or more. The method is selected from the group in which the chiral auxiliary consists of (+)-2,3-dibenzoyl-D-tartaric acid, (+)-O, O'-di-p-toluoil-D-tartaric acid, and combinations thereof. The method according to claim 1, wherein the S-type optical isomer of the compound represented by Chemical Formula 1 is obtained in an excess amount of a mirror image. The method is selected from the group in which the chiral auxiliary consists of (-)-2,3-dibenzoyl-L-tartaric acid, (-)-O, O'-di-p-toluoil-L-tartaric acid, and combinations thereof. The method according to claim 1, wherein the R-type optical isomer of the compound represented by Chemical Formula 1 is obtained in an excess amount of a mirror image. The method according to claim 1, wherein the halogen is one or more selected from the group consisting of F, Cl, Br, and I. R ₁ is one selected from the group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group.
The method of claim 5, wherein R _{2 is hydrogen.} R ₁ is a methyl group
R ₃ and R ₇ are hydrogen
The method of claim 6, wherein R ₄ , R ₅ , and R ₆ are one selected from the group consisting of alkyl groups F, Cl, Br, I, and C _1-6. R ₄ and _{R 6} are F,
R ₅ is a methyl group
The method according to claim 7, wherein the compound is N- {4-[(1R / S) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide. The method of claim 1, wherein the polar aprotic solvent is one or more selected from the group consisting of ethyl acetate, tetrahydrofuran, acetonitrile, acetone, and combinations thereof. The method of claim 9, wherein the polar aprotic solvent is acetone. The method of claim 1, wherein the polar aprotic solvent is added in an amount that dissolves all the mixtures. 11. The method of claim 11, wherein the polar aprotic solvent is 5 to 15 multiples (v / w) of the total weight of the stereoisomer mixture. The method of claim 1, wherein in the method the mixing is carried out by increasing the temperature of the mixture to 40 ° C. to 70 ° C., the boiling point of the solvent, or the boiling point of the solvent mixture. The method according to any one of claims 1 to 13, wherein the equivalent ratio of the chiral auxiliary to 1 molar equivalent of the stereoisomer mixture is 0.5 to 2.0 equivalents. The method of claim 14, wherein the chiral auxiliary equivalent to 1 molar equivalent of the stereoisomeric mixture is 0.8 to 1.5 equivalents. The method according to claim 1 , wherein the stereoisomer mixture has a ratio of R-type isomer: S-type isomer of 1: 3 to 1: 9. The method according to claim 1 , wherein the step of adjusting the ratio of the R-type isomer: S-type isomer is to adjust the ratio to 4: 6 to 6: 4. A method for producing a compound having a structure represented by the chemical formula 3a or 3b.
The method is a step of chirally dividing a stereoisomer mixture of a compound having the structure represented by the chemical formula 1 by the method according to any one of claims 1 to 13; and the divided stereoisomers. Including the step of converting to a compound having the structure represented by the chemical formula 3a or 3b.

The R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are H; -NH ₂ ; an alkyl group of _{C 1-6} ; an alkenyl _{group of C 2-6; C.} One selected from the group consisting of _{2-6 alkynyl groups; and halogens.}
R ₁ and R ₂ are methods for producing a compound having a structure represented by the chemical formula 3a or 3b, which has different substituents from each other. The compound having the structure represented by the chemical formula 3a is (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-tri). Fluoromethyl-pyridine-3-yl) -acrylamide,
The method according to claim 18 , wherein the compound having the structure represented by the chemical formula 1 is N- {4-[(1R / S) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide. .. The step of converting the divided stereoisomer into a compound having the structure represented by the chemical formula 3a or 3b is N- {4-[(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfon. The method of claim 18 , comprising coupling amide (INT-3) with 3- (2-propyl-6-trifluoromethyl-pyridine-3-yl) -acrylic acid (INT-7).