TW201726585A - Method for chiral resolution of N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives by using polar aprotic solvent - Google Patents

Abstract

Disclosed is a method for chiral resolution of a stereoisomer mixture, which includes mixing a stereoisomer mixture of a compound having an asymmetric carbon atom to which an amine group is bound with a chiral auxiliary. The chiral auxiliary is 2,3-dibenzoyl tartaric acid or O,O'-di-p-toluoyl tartaric acid. According to the method, it is possible to obtain an optical isomer having a high level of optical purity. In addition, according to the present disclosure, it is possible to adjust the ratio of the stereoisomer mixture contained in the mother liquor by recovering the optical isomer. Therefore, the method is useful for recovering a single type of optical isomer with high purity in the pharmaceutical or drug manufacture field. The method is also useful for carrying out racemization of the mother liquor used for another reaction.

Description

Method for the palmitic resolution of N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives by using a polar aprotic solvent

The present invention relates to a method for the palmitic resolution of N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives.

Recently, there has been an increasing demand for stereoscopically pure compounds. One of the important uses of the pure stereoisomers is the use as an intermediate in the pharmaceutical field. For example, it has gradually emerged that a single enantiomerically pure drug has many advantages over a racemic drug mixture. These advantages generally include fewer side effects associated with mirror-isomerically pure compounds and higher efficacy [see, Stinson, S.C., Chem Eng News, Sept. 28, 1992, pp. 46-79].

For example, triadimenol may have 4 types of isomers, wherein the (-)-(1S, 2R)-isomer has a (+)-(1R, 2R)-isomer compared to the (+)-(1R, 2R)-isomer The higher activity, and the (-)-(1S, 2S)-isomer have higher activity than the (+)-(1R, 2S)-isomer. It is known that the (1R, 2R)-isomer of dichlorobutrazole has the highest activity among the four isomers of benzyl chlorotriazole alcohol. It is also known that the (+)-(2S,4S)- and (-)-(2S,4R)-isomers of etaconazole have higher sterilization effects than other isoxadiazole isomers. .

Therefore, if only one highly active isomer can be selectively produced, a small amount of isomer can be used to obtain a high effect, and thus reduce environmental pollution caused by the use of chemicals. In particular, in the case of pharmaceuticals, it is important to selectively prepare a single isomer when any of the isomers exhibit toxicity to humans.

Therefore, in the pharmaceutical field, pharmaceutical and biochemical related industries, the preparation of optically pure compounds has become an extremely important goal to improve the pharmaceutical efficacy per unit dose and to avoid side effects and cause medicinal damage.

For example, it is shown that a N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivative containing a vanilloid antagonist is effective if it is a pure stereoisomer [see WO2008-013414 A1, WO2007 -133637 A2, WO2007-129188 A1, WO2010-010934 A1].

A known method for preparing a single isomer of the N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivative is an asymmetric synthesis using an Elman adjuvant. For example, WO2008-013414 A1, WO2007-133637 A2, WO2007-129188 A1 and WO2010-010934 A1 disclose a method for preparing a desired stereoisomer by introducing an Elman adjuvant and using it to induce asymmetry reduction (reduction). However, the above process requires maintaining a low temperature to increase the excess of the image isomer (% ee), risk due to excess hydrogen and heat dissipation during the reaction quenching, and excessive organic and inorganic waste after the reaction is quenched, which results in treatment. Program and cost constraints. [References] [Patent Documents] WO2008-013414 A1 WO2007-133637 A2 WO2007-129188 A1 WO2010-010934 A1

[Technical Problem] Although asymmetric synthesis of N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives The law has so far reported that commercially viable methods have not been established due to cost-effectiveness and safety. Therefore, in view of cost-effectiveness and processing safety, the technical problem to be solved by the present disclosure is to provide a novel method for interpreting a mixture of stereoisomers using a polar aprotic solvent.

[Technical Solution] In a general aspect, there is provided a high optical activity palm with a salt of N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivative The auxiliary agent is a method in which an N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivative represented by the following Chemical Formula 1 is resolved into individual compounds having high optical purity. [Chemical Formula 1]

More specifically, it provides a high optical purity N-[4-(1-amino group) by (R,S)-N-[4-(1-aminoethyl)-phenyl]-sulfonamide A method of ethyl)-phenyl]-sulfonamide, the method comprising: reacting (R,S)-N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivative with Optically active palmitic adjuvants are mixed to form (R)- or (S)-type optically active N-[4-(1-aminoethyl)-phenyl]-sulfonamide dimercapto tartrate or a solvent thereof And separating the optically active N-[4-(1-aminoethyl)-phenyl]-sulfonamide salt or solvate with a base to obtain an optically active N-[4-(1-amine) Base ethyl)-phenyl]-sulfonamide.

According to this method, the N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivative can be easily resolved into an individual compound having high optical purity.

N-[4-(1-Aminoethyl)-2,6-difluorophenyl]-methanesulfonamide (N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide) The general name of the compound represented by the following Chemical Formula 2 is known to be useful for preparation as TRPV1 (transient receptor potential channel subfamily V member 1 or capsaicin receptor ( Capsaicin receptor), an intermediate of the compound of the antagonist vanilloid receptor 1). [Chemical Formula 2]

As shown in Chemical Formula 2, N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide is a palm compound in which the carbon atom is bonded to an amine group. As a palm center.

[Advantageous Effects] According to the palm separation method of the present disclosure, a mixture of stereoisomers (especially a mixture of stereoisomers of a compound having a palm center bonded to an amine group) can be easily resolved into Individual high optical purity compounds. Compared to the asymmetric synthesis using Elman adjuvant, the method provides improved safety and cost-effectiveness, performs palmar resolution to at least optical purity of the same optical purity as asymmetric synthesis, and is recovered and reused. Salts are characterized by high cost-effectiveness and environmental friendliness. Therefore, the method can be used to prepare a starting material for a palm-like analytical compound in the field of pharmaceuticals and cosmetics.

In particular, the method provides higher efficiency in accordance with one aspect of the present disclosure than the asymmetric synthesis of the conventional Elman adjuvant, thus providing a desired stereoisomer at least equal to the optical purity of the conventional method, and It shows high efficiency and high cost efficiency in mass production.

Furthermore, the mother liquor of the mixture of stereoisomers can be controlled or converted according to the teachings of the present disclosure as a racemate containing an S-isomer and an R-isomer in a ratio of about 1:1. It is also possible to race off to high purity by only the palmar analysis of the stereoisomer compound without using any additional racemization reaction. Therefore, the method according to the present disclosure can directly use the mother liquor for another palm analysis step without any additional means. As a result, unlike the conventional racemic reaction, it is possible to provide high cost efficiency without loss of the compound.

In one aspect, a method for the palmar resolution of a mixture of stereoisomers is provided, which comprises mixing a mixture of stereoisomers of a compound with a palm adjuvant in the presence of a solvent, in mirror image isomerism The non-Spiegelmer salt of the compound is precipitated with the palm adjuvant in a bulk excess.

According to a specific embodiment, the palm adjuvant may be at least one selected from the group consisting of 2,3-dibenzoyl tartaric acid, O, O'-di- p -toluene. O, O'-di-p-toluoyl tartaric acid, stereoisomers thereof, and combinations thereof.

As used herein, the term "enantiomeric excess" generally means an increase in the proportion of any mirror image isomer, and therefore does not only mean that one of the mirror isomers is excessive compared to the racemic mixture and is comparable to Any of the mirror image isomers having a different mixture than the 1:1 mirror isomer ratio (the same ratio is a racemic mixture). According to a specific embodiment, "one image isomer excess" may correspond to the following image isomer excess (%ee): 80% or more, 82% or more, 84% or more, 86% or Above, 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. Similarly, the term "high optical purity" as used herein is well known to those skilled in the art. According to a specific embodiment, the term "high optical purity" may correspond to the following image isomer excess: 80% or more, 82% or more, 84% or more, 86% or more, 88% or Above 90% or more, 92% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or the above.

Chiral auxiliary as used herein is well known to those skilled in the art. In particular, the palmitic adjuvant means a compound that is temporarily incorporated into an organic compound synthesis process to control the stereochemical results of the synthesis of the organic compound. The palmar adjuvant can be used as an adjuvant to determine at least one stereoselective response to a series of reactions (see the Wikipedia Assistants page on Wikipedia, http://en.wikipedia.org/wiki/ Chiral_Auxiliary) . The "palmative adjuvant" used herein can be interchanged with "palm acid".

According to another specific embodiment, the 2,3-dibenzimidyl tartaric acid may be (+)-2,3-dibenridyl-D-tartaric acid ((+)-2,3-dibenzoyl-D-tartaric Acid) or (-)-2,3-dibenzoyl-L-tartaric acid, which are optical isomers of each other. In addition, O,O' -di- p -tolylmethyl tartaric acid may be (+)- O, O'-di- p -tolylmethyl-D-tartaric acid ((+)- O, O'-di - p -toluoyl-D-tartaric acid) or (-)- O, O'-di- p -tolylmethyl-L-tartaric acid ((-)- O, O'-di- p- toluoyl-L- Tartaric acid), which are optical isomers of each other. If it is such a tartaric acid derivative, the D-isomer and the L-isomer may be used singly or in combination. However, each isomer is preferably used singly. When the method of the present disclosure is combined with the D- and L-optical isomers of the tartaric acid derivative, the optical purity may be reduced as compared with the optical purity obtained when the respective D- and L-isomers are used alone.

According to still another embodiment, the mixture of stereoisomers can be a mixture of stereoisomers of a compound having an asymmetric carbon atom. In particular, according to still another embodiment, the compound having an asymmetric carbon atom may have an amine group bonded thereto. In particular according to still another embodiment, the compound may have, in addition to the amine group, a substituted or unsubstituted phenyl group bonded to one of the asymmetric carbon atoms. Further, according to still another specific embodiment, the compound having an asymmetric carbon atom may be a compound represented by Chemical Formula 1.

According to still another embodiment, the method may be a method for obtaining an R-type or S-type optical isomer having a mixture of stereoisomers of high optical purity.

According to still another specific embodiment, when the palm adjuvant is selected from (+)-2,3-dibenyl-D-tartaric acid, (+)- O, O' -di- p- Any of the group consisting of tolylmethyl-D-tartaric acid and combinations thereof, may be a method for obtaining an optical S-type optical isomer of a compound in the form of an excess of Spiegelmer.

According to still another specific embodiment, when the palm adjuvant is selected from (-)-2,3-dibenyl-L-tartaric acid, (-)- O, O' -di- p- Any of the group consisting of tolylmethyl-L-tartaric acid and combinations thereof, may be used to obtain a compound R-type optical isomer in an excess of the Spiegelmer.

According to still another specific embodiment, the compound may be represented by Chemical Formula 1. [Chemical Formula 1] Wherein each _{R 1, R 2, R 3} , R 4, R 5, R 6 , and R ₇ represents any one selected from the group consisting of H, -NH _2, C _1-6 alkyl, C _C2-6 alkenyl, C _a group consisting of _2-6 alkynyl and halogen, and R ₁ and R ₂ have different substituents.

According to a specific embodiment, the halogen may be at least one selected from the group consisting of F, Cl, Br, and I.

According to still another embodiment, R ₁ may be any group selected from the group consisting of methyl, ethyl, propyl, butyl, and pentyl, and R ₂ may be H.

According to still another embodiment, R ₁ may be a methyl group, each of R ₃ and R ₇ may be H, and each of R ₄ , R ₅ and R ₆ may be selected from the group consisting of F, Cl, Br, I. And a group consisting of C _1-6 alkyl groups.

According to still another embodiment, each of R ₄ and R ₆ may be F, and R ₅ may be methyl.

According to still another embodiment, the compound can be N-{4-[(1R/S)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide (N-{4 -[(1R/S)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide).

According to still another embodiment, the solvent can be a polar aprotic solvent.

According to still another embodiment, the polar aprotic solvent can be at least one selected from the group consisting of ethyl acetate, tetrahydrofuran, acetonitrile, acetone, and combinations thereof. In particular, the polar aprotic solvent can be acetone.

According to still another embodiment, the solvent is added in an amount that will dissolve all of the mixture. In particular, according to still another embodiment, the solvent may be added in an amount of from 2 to 80 times the total weight of the mixture of stereoisomers, in particular from 5 to 30 times, more particularly from 5 to 15 times, and even more particularly 10 times (volume (solvent) / weight (stereoisomer, or (v/w)). According to still another embodiment, the solvent may be added in an amount corresponding to the following multiples of the total weight of the mixture of stereoisomers: At least 2, at least 5, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70 or at least 80, or at most 80, at most 70, at most 60 times, up to 50 times, up to 40 times, up to 30 times, up to 20 times, up to 15 times, up to 10 times or up to 5 times.

According to still another embodiment of the method, the step of mixing can be carried out at 40-70 ° C, the boiling point of a solvent, or by increasing the temperature to the boiling point of a solvent mixture.

According to still another embodiment, the mixing step can be carried out by increasing the temperature while stirring for 1-4 hours.

According to still another embodiment, the agitation can be agitated under reflux.

According to still another embodiment, the temperature may be 30 ° C or higher, 40 ° C or higher, 50 ° C or higher, 60 ° C or higher or 70 ° C or higher, or 70 ° C or lower, 60 ° C or lower, 50 ° C or lower, 40 ° C or lower or 30 ° C or lower. In particular, the temperature may be from 40 to 60 ° C, more particularly from 45 to 55 ° C, and even more particularly 50 ° C.

According to still another embodiment, the agitation can be carried out for at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours or at least 5 hours, or up to 6 hours, up to 5 hours, up to 4 hours, up to 3 hours, at most 2 hours or up to 1 hour. In particular, the agitation can be carried out for 2-4 hours, more particularly 2.5-3.5 hours, and even more particularly 3 hours.

According to still another embodiment, the palm adjuvant is used in an amount of from 0.5 to 2.0 equivalents per equivalent of the mixture of stereoisomers, particularly from 0.8 to 1.5 equivalents.

According to still another embodiment, the palm adjuvant is used in an amount based on 1 mole of the equivalent of the stereoisomer mixture: at least 0.10 eq., at least 0.2 eq., at least 0.3 eq., at least 0.4 eq , at least 0.5 eq., at least 0.6 eq., at least 0.7 eq., at least 0.8 eq., at least 0.85 eq., at least 0.90 eq., at least 0.95 eq., at least 1.0 eq., at least 1.05 eq., at least 1.1 eq. , at least 1.15 eq., at least 1.2 eq., at least 1.3 eq., at least 1.4 eq., at least 1.5 eq. or at least 2.0 eq., or at most 2.0 eq., up to 1.5 eq., up to 1.4 eq., up to 1.3 Eq., up to 1.2 eq., up to 1.14 eq., up to 1.1 eq., up to 1.05 eq., up to 1.0 eq., up to 0.95 eq., up to 0.90 eq., up to 0.85 eq., up to 0.8 eq., up to 0.7 Eq., up to 0.6 eq., up to 0.5 eq., up to 0.4 eq., up to 0.3 eq., up to 0.2 eq. or up to 0.10 eq.

According to still another embodiment, the mixture of stereoisomers may have an R-isomer of 1:9 to 9:1: S-isomer ratio, which comprises any between 1:9 and 9:1. Integer ratio. In particular, according to still another embodiment, the mixture of stereoisomers may have the following R-isomers: S-isomer ratio: 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, or 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 Above or 1: 9 or above.

According to still another embodiment, after the step of precipitating the Spiegelmer excess of the non-Spiegelmer salt of the compound [Chemical Formula 1] with a palmity adjuvant, the method may further comprise the step of recovering the The precipitated non-Spiegelmer salt and the R-isomer:S-isomer ratio of the mixture of stereoisomers contained in the mother liquor are adjusted to 3:7 to 7:3. In particular, according to still another embodiment, the step of adjusting the R-isomer: S-isomer ratio can be carried out by adjusting the ratio to: 3: 7 to 7: 3, 4: 6 to 6 : 4,7 : 8 to 8 : 7,9 : 11 to 11 : 9,12 : 13 to 13 : 12 or about 5 : 5 .

In another aspect, a stereoisomer of a compound is provided which is isolated and obtained from a mixture of stereoisomers according to the methods of the present disclosure, wherein the stereoisomer has the following image isomer excess: 80% ee or above, 82% ee or above, 84% ee or above, 86% ee or above, 88% ee or above, 90% ee or above, 92% ee or above, 94 % ee or above, 96% ee or above, 97% ee or above, 98% ee or above, or 99% ee or above.

According to a particular embodiment, the stereoisomer can be N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide (N-{4- [(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide) or N-{4-[(1S)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide (N-{4-[(1S)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide).

The term "asymmetric carbon atom" as used herein means a carbon atom in the molecule that binds four different atoms, atomic groups or functional groups. If it is a compound having an asymmetric carbon atom, it has optical rotatability, optical activity or optical isomers.

The term "stereoisomer mixture" as used herein means a mixture of two of the image isomers of the optically active isomer compound, wherein the mixture may have a mixture ratio of 1:1 (corresponding to a racemic mixture), or An integer ratio between 1:10 and 10:1. According to another specific embodiment, the mixture of stereoisomers may be synthetic or may be a mixture having an unknown ratio of R-optical isomers to S-optical isomers. According to the method of the present disclosure, the ratio of any optical isomer of the R- and S-isomers can be significantly increased. Therefore, optical isomers of a desired type having high optical purity can be obtained regardless of the ratio of mixing.

N-[4-(1-Aminoethyl)-2,6-difluorophenyl]-methanesulfonamide as used herein means a compound designated as CAS No. 1202743-51-8 having a molecular weight of 250.27. Da, and can be used interchangeably with INT-2 below. It may be a mixture of stereoisomers containing the R-isomer and the S-isomer which are intermixed.

According to another specific embodiment, N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}-methanesulfonamide hydrochloride (N-{4-[( 1R)-1-aminoethyl]-2,6-difluorophenyl}-methanesulfonamide hydrochloride means a compound designated as CAS No. 956901-23-8 and having a molecular weight of 286.73 Da, and N-{4-[(1R)-1 -Aminoethyl]-2,6-difluorophenyl}-methanesulfonamide forms the corresponding to CAS No. 957103-01-4. Further, as used herein, it is used interchangeably with the R-isomer of INT-3 below.

According to still another embodiment, 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (3-(2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid) corresponds to CAS number 1005174-17-3 and has a molecular weight of 259.22 Da.

According to still another embodiment, (R)-N-[1-(3,5-difluoro-4-methylsulfonylamino-phenyl)-ethyl]-3-(2-propyl- 6-Trifluoromethyl-pyridin-3-yl)-propenylamine ((R)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2- Propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide) (PAC-14028) corresponds to CAS number 1005168-10-4 and has a molecular weight of 491.47 Da.

In still another aspect, the R- or S-isomer of INT-3 is obtained by a process comprising the steps of: INT-2 (N-[4-(1-aminoethyl)-2) , 6-difluorophenyl]-methanesulfonamide) is mixed with a palmitic adjuvant; a polar aprotic solvent is added to the resulting mixture, which corresponds to 10 times the weight of INT-2 (v/w) The mixture is refluxed at 30-70 ° C for 1-4 hours for the mixed solution containing the polar aprotic solvent added thereto; cooling the agitated mixture; and filtering the obtained by the cooling step The solid was taken to obtain the INT-3 chiral acid salt.

According to a specific embodiment, the cooling step can be carried out by refluxing the mixture to 15-30 ° C after refluxing.

According to another specific embodiment, the cooling step can be carried out by cooling the mixture to a temperature of: 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; or 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 ° C or lower.

According to still another embodiment, the method may further comprise the step of isolating the palmitic acid from the generated INT-3 palmitic acid salt. In particular, the separation step can be carried out by introducing the INT-3 palmitic acid salt with 5 times the weight of the salt and 2 eq. of 28 vol% ammonia water; stirring the obtained suspension 20 Filtration was carried out for 50 minutes; and the residual water was removed under reduced pressure under vacuum to obtain the R- or S-isomer of INT-3.

In still another aspect, a method for parsing a mixture of stereoisomers is provided, comprising the steps of: (1) mixing a mixture of stereoisomers of a compound with a palm adjuvant, the compound There is an asymmetric carbon atom bonded to an amine group.

According to a particular embodiment, the compound can be N-{4-[(1R/S)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide.

According to another specific embodiment, the palm adjuvant in step (1) may be at least one selected from the group consisting of 2,3-dibenyl tartaric acid, O, O'-di- p -tolylmethyl A group consisting of tartaric acid, its stereoisomers, and combinations thereof.

According to still another embodiment, the method may further comprise the step (2) following the step (1): adding a solvent to the mixture of the step (1).

According to still another embodiment, the solvent can be a polar aprotic solvent.

According to still another embodiment, the method may further comprise the step (3) of agitating the mixed solution under reflux containing the solvent added thereto.

According to still another embodiment, the agitation of step (3) can be carried out for at least 30 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 3.5 hours or at least 4 hours, or Up to 5 hours, up to 4.5 hours, up to 4 hours, up to 3.5 hours, up to 3 hours, up to 2.5 hours, up to 2 hours, up to 1.5 hours, up to 1 hour, or up to 30 minutes.

According to still another embodiment, the agitation of step (3) can be carried out at the following temperatures: 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 or higher, or 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 20 ° C or lower.

According to still another embodiment, the method may further comprise the step (4) of cooling the mixture of step (3).

According to still another embodiment, the method may further comprise the step (5): filtering the solid formed by cooling to obtain a non-Spiegelmer salt of the compound. In particular, according to still another embodiment, the non-Spiegelmer salt of the compound can be a INT-3 non-Spiegelmer salt.

According to still another embodiment, the method may further comprise the step (6) of removing or isolating the palmitic acid from the produced non-Spiegelmer salt.

According to still another embodiment, step (6) may comprise step 1): introducing water and aqueous ammonia to the INT-3 non-Spiegelmer salt. In particular, according to still another embodiment, in step (6), the water system is used in an amount of at least 2 times, at least 3 times, at least 4 times, at least 5 by weight of the INT-3 isomere salt salt. Times, at least 6 times or at least 7 times, or up to 7 times, up to 6 times, up to 5 times, up to 4 times, up to 3 times, or up to 2 times. In particular, according to still another embodiment of the present disclosure, in step (6), the aqueous ammonia may be an aqueous solution of the following ratio of ammonia: at least 20 vol%, at least 24 vol%, at least 28 vol%, at least 32 vol% , at least 36 vol% or at least 40 vol%, or up to 40 vol%, up to 36 vol%, up to 32 vol%, up to 28 vol%, up to 24 vol% or up to 20 vol%. In particular, in accordance with still another embodiment of the present disclosure, in step (6), the aqueous ammonia is introduced in an amount of at least 0.5 eq., at least 1 eq., at least 1.5 eq., at least 2 eq., at least 2.5 eq. Or at least 3 eq., or up to 4 eq., up to 3.5 eq., up to 3 eq., up to 2.5 eq., up to 2 eq., up to 1.5 eq., up to 1 eq. or up to 0.5 eq.

According to still another embodiment, step (6) may further comprise step 2) after step 1): agitating the mixed solution. In particular, according to still another embodiment, the agitation in step (6) is carried out for at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 60 minutes or at least 70 minutes. , or up to 70 minutes, up to 60 minutes, up to 50 minutes, up to 40 minutes, up to 30 minutes, up to 20 minutes or up to 10 minutes.

According to still another embodiment, step (6) may further comprise step 3): filtering the suspension obtained by agitation.

According to still another embodiment, step (6) may further comprise step 4): removing water from the filtered suspension under reduced pressure vacuum to obtain the R- or S-isomer of INT-3.

In still another aspect, there is provided a method for the preparation of a compound represented by the following Chemical Formula 3a or 3b, which comprises: performing a palmar resolution of a mixture of stereoisomers of a compound using the method of the present disclosure [Chemical Formula 1] And converting the resolved stereoisomer to a compound represented by Chemical Formula 3a or 3b: [Chemical Formula 3a] [Chemical Formula 3b] Wherein each _{R 1, R 2, R 3} , R 4, R 5, R 6 , and R ₇ represents any one selected from the group consisting of H, -NH _2, C _1-6 alkyl, C _C2-6 alkenyl, C _a group consisting of _2-6 alkynyl and halogen, and R ₁ and R ₂ have different substituents. This conversion step is described in Korean Patent Application No. 10-2009-7004333.

According to a specific embodiment, the compound of the formula 3a may be (R)-N-[1-(3,5-difluoro-4-methylsulfonylamino-phenyl)-ethyl]-3 -(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (PAC-14028), and the compound [Chemical Formula 1] can be N-{4-[(1R) /S)-1-Aminoethyl]-2,6-difluorophenyl}methanesulfonamide.

According to another embodiment, the step of converting the resolved stereoisomer to the compound of formula 3a or 3b can be accomplished by coupling N-{4-[(1R)-1-aminoethyl]- 2,6-Difluorophenyl}methanesulfonamide (INT-3) and 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)acrylic acid (3-(2-propyl-) 6-trifluoromethyl-pyridin-3-yl)acrylic acid) (INT-7).

The resolved stereoisomers by the method of the present disclosure can be used as an intermediate for the preparation of the novel drug disclosed in Korean Patent Application No. 10-2009-7004333 by defining the stereoisomer therein The substance reacts. Accordingly, in yet another aspect, there is provided a method of preparing a novel pharmaceutical product disclosed in Korean Patent Application No. 10-2009-7004333, or a novel pharmaceutical product obtained therefrom, by using the analytical stereoisomer.

In still another aspect, there is provided (R)- obtained by the method of the present disclosure and having 96% or more, 97% or more, 98% or more, or 99% or more of the image isomer excess. N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridine-3- Base) - acrylamide.

In still another aspect, there is provided a TRPV1 antagonist comprising (R)-N-[1-(3,5-difluoro-4-methanesulfonylamino) obtained as an active ingredient by the method of the present disclosure. -Phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-propenylamine (PAC-14028). The TRPV1 antagonist can be used as a pharmaceutical composition for preventing or treating the diseases described herein below.

In still another aspect, there is provided a pharmaceutical composition comprising (R)-N-[1-(3,5-difluoro-4-methylsulfonylamino-phenyl)- Ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-propenylamine, an optical isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof A vector for preventing or treating a disease associated with pathological stimulation and/or abnormal expression of a vanilloid receptor, which is selected from the group consisting of pain, joint inflammatory disease, HIV-related nerve Disease, nerve damage, neurodegeneration, stroke, urinary incontinence, cystitis, gastroduodenal ulcer, intestinal fistula (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastroesophageal reflux (GERD), cloning Disease, asthma, chronic obstructive pulmonary disease, cough, atopic/allergic/inflammatory skin disease, psoriasis, itching, pruritus, skin irritation, inflammation of the eyes or mucous membranes, misophonia, tinnitus, vestibular hypersensitivity Reaction, episodic dizziness, myocardial ischemia, hirsutism, alopecia, rhinitis and pancreatitis.

According to a specific embodiment, the pain may be selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, tooth pain, Fibromyalgia, myofascial pain syndrome, lower back pain, migraine and other types of headache or pain associated with the disease.

In still another aspect, an optical resolution kit is provided comprising: a palm adjuvant; a polar aprotic solvent; and a palm aid adjuvant user manual.

According to a specific embodiment, the palm adjuvant may be at least one selected from the group consisting of 2,3-dibenyl tartaric acid, O, O'-di- p -tolylhydrazide tartaric acid, and its stereoisomers. And the group consisting of its combination.

According to another embodiment, the palm adjuvant is used in an amount of from 0.5 to 2.0 eq. per optical equivalent of the stereoisomer mixture.

According to still another embodiment, the salt-forming adjuvant compound is used in an amount of from 0.8 to 1.5 eq. per optical equivalent of the stereoisomer mixture.

According to still another embodiment, the instruction manual comprises the following: when the optical resolving agent is used, the optically resolved stereoisomer mixture is present in an amount of from 0.5 to 2.0 eq. Especially 0.8-1.5 eq.).

According to still another embodiment, the instruction manual may comprise the following: when the palm adjuvant is used, the palm adjuvant is mixed with the stereoisomer mixture in the presence of a polar aprotic solvent.

According to yet another embodiment, the user manual may contain content relating to a palm-like analytical method for use in a mixture of stereoisomers of the present disclosure.

[Embodiment Mode for Carrying Out] The embodiment and the test embodiment will now be described more fully below. The following examples and test examples are for illustrative purposes only and the scope of the disclosure should not be construed as being limited to the exemplary embodiments shown. In addition, those skilled in the art will appreciate that various changes in form and detail may be made without departing from the scope of the invention. [Comparative Test Example 1] Determine the optical purity of a conventional asymmetric synthesis process

A conventional asymmetric synthesis process is carried out in accordance with Reaction Scheme 1 below. [Reaction Framework 1]

N-{2,6-Difluoro-4-[1-(2-methyl-propane-2-sulfonanylimino)-ethyl]-phenyl}-methanesulfonamide (1 Eq.) was added to tetrahydrofuran (THF, 20 mL) corresponding to 10 times its weight and dissolved therein. Next, NaBH ₄ (4 eq.) was further dissolved in the resulting solution, and then reacted at the temperature listed in Table 1 for 10 hours. Then, CH ₃ OH was added dropwise until no more evolution of hydrogen gas.

After the resulting mixture was concentrated under reduced pressure, it was purified by chromatography to obtain N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfynyl) N-{2,6-difluoro-4-[1-(2-methyl-propan-2sulfynylamino)-ethyl]-phenyl}-methanesulfonamide). After an excess of 4 M HCl in dioxane solution was added dropwise, the resulting mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue remaining after the preparation was purified by recrystallization from acetone to obtain (R)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide HCl. Salt ((R)-N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]-methanesulfonamide HCl salt).

The resulting salt was determined to be an excess of the mirror image isomer by the same procedure as the following test example, and the results are shown in Table 1. [Table 1]

According to the conventional method, it is necessary to continuously maintain the temperature at -40 ° C or lower for 10 hours to obtain an optical activity of 96% or more as shown in Table 1. In contrast, according to the present disclosure, the same degree of optical activity is obtained only by a process comprising a solvent agitation and purification at a temperature of 50 °C. Thus, it can be seen that the disclosed method is significantly more cost effective than conventional methods. Further, when the reaction was extended to an industrial plant unit, it was easier to maintain the temperature at 50 ° C for 10 hours as compared with the temperature of -40 ° C. The result is that the disclosed method is more suitable for expanding the scale of the reaction compared to conventional methods.

In addition, if a conventional method uses 2-4 eq. of sodium borohydride, an excessive amount of explosive hydrogen gas is generated during the quenching of the reaction, causing heat loss. This corresponds to a process that involves an extremely dangerous reaction. Conversely, the present disclosure provides a unique effect of producing commercially available optically active isomers without the risk of hazardous processes such as excessive generation of explosive hydrogen or heat loss.

Therefore, it can be seen from the above results that the present disclosure corresponds to a method involving a more cost effective and safe process than the conventional method. [Comparative Test Example 2] Analysis of type and determination of optical purity when using polar protic solvent

N-[4-(1-Aminoethyl)-2,6-difluorophenyl]-methanesulfonamide according to the method described in Bioorganic & Medicinal Chemistry (15 (18), 6043-6053; 2007) (Mixing of the R-isomer and the S-isomer, R: S = 1 : 1) was prepared. The N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide obtained in the ratio of 1 eq. : 1 eq was mixed with each of the opticals listed in Table 2 below. Analytical agent (Sigma-Aldrich). Then, a solvent (different protic solvent of Table 2 below) is 10 times the weight of N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide It is added to the resulting mixture. The solvent was added to the mixed solution at 50 ° C for 3 hours and then cooled to 25 ° C. The resulting solid was filtered through a Buchner funnel to obtain each N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide palm acid salt. .

For each of the N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide palmitic acid salts, 5 times the amount of water and 2 eq of the salt was introduced. 28 vol% ammonia. Next, the reaction mixture was agitated for 30 minutes to provide a suspension which was filtered through a Buchner funnel. Then, the residual water is removed under reduced pressure under vacuum to obtain each N-[4-((1R)-1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide and N- [4-((1S)-1-Aminoethyl)-2,6-difluorophenyl]-methanesulfonamide.

The optical purity (Spiegelmer excess) of the resulting INT-3 was analyzed using a Shiseido Chiral CD-Ph 4.6 mm x 250 mm, 5 μm. As the mobile phase, a mixed solution of 0.5 mol/L sodium perchlorate and methanol (75 vol%: 25 vol%) was used. The ratio of each palmitic acid salt isolated as a solid was determined using the Waters 32695 Alliance HPLC under the following conditions. The asterion isomer excess (ee%) of each salt can be calculated according to the following mathematical formula 1 based on the ratio of each salt.

The results for the respective salt ratios are shown in Table 2 below. <HPLC conditions> 1. Column temperature: 35 ° C 2. Flow rate: 0.5 mL/min. 3. Detection: 220 nm 4. Rt (min.): 20.4 (R-image isomer %), 18.9 (S - Mirror isomer %) [Mathematical Formula 1] Mirror Isomer excess (% ee) = [(The desired isomer) - (trans-isomer)] / [(The desired isomer) + (trans-isomer)] x 100 [Table 2] * When an L-type palmarity adjuvant is used, the R-isomer and the S-isomer system are obtained in opposite proportions.

From the above results, it can be seen that when a polar protic solvent other than the one disclosed in the present disclosure is used, a D-type palm adjuvant is used to resolve and obtain the R-isomer. Further, when a mixed solvent containing 1:1 isopropanol (as a polar protic solvent) and acetone (as an aprotic solvent) is used, the R-isomer and the S-isomer system are obtained in the same ratio. Thus, it can be seen that when solvent mixtures having different properties are used, it is not possible to perform stereoisomer mixture resolution. [Test Example 1] Determination of analysis when using a polar aprotic solvent for analysis

Comparative test The method described in Example 2 was carried out except that the polar aprotic solvent described in Table 3 below was used. After the test, the ratio of each isomer separated into a solid was determined under the HPLC conditions described in Comparative Test Example 2. The results are shown in Table 3 below. [table 3]

From the above results, it can be seen that when a D-type palm adjuvant and a mixture of stereoisomers are reacted in the presence of the polar aprotic solvent of the present disclosure, a higher proportion can be obtained in most polar aprotic solvents. S-stereoisomer. In the case of dimethylformamide and dimethylhydrazine, N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide palm acid salt is The solvent is completely dissolved and does not separate into a solid. Therefore, it is impossible to determine whether the salt is resolved.

Among the polar aprotic solvents, acetone provides the highest yield of the S-isomer. Therefore, the palmity adjuvant equivalent is adjusted and the R-isomer in the stereoisomer mixture: The S-isomer ratio is also adjusted in the presence of acetone to determine the difference The proportion and yield of the constituent compounds. [Test Example 2] When using an acetone solvent, the ratio and yield were determined according to the equivalent of the palm adjuvant.

The method described in Comparative Test Example 2 was carried out except that acetone was used as a solvent and different equivalents of the palmitic adjuvant were used as shown in Table 4 below. The ratio of isomers separated into solids was determined under the HPLC conditions of Comparative Test Example 2. Further, the reaction yield was calculated according to Mathematical Formula 2 below. The results are shown in Table 4. [Mathematical Formula 2] Yield (%) = (Actual Quantity / Theoretical Quantity) x 100 Actual Quantity: Actually Obtained Product Amount Theoretical Quantity: The maximum amount of product obtainable from a specific amount of reactant [Table 4] * When an L-type palmarity adjuvant is used, the R-isomer and the S-isomer system are obtained in opposite proportions.

From the above results, it can be seen that solid isomers of different ratios and yields can be obtained according to the equivalents of the stereoisomer mixture and the palmitic adjuvant. When the equivalent weight of the palmitic adjuvant of the mixture of the stereoisomers is 1 eq. or more, the resolution of the S-isomer is performed and when the palm adjuvant is used in an amount of 1.2 eq. The ratio of isomers is the highest. Further, if the S-isomer is resolved, the yield of the S-isomer is highest when the palm adjuvant is used in an amount of 1.2 eq. [Test Example 3] Optical purity and yield were determined based on the ratio of R:S of the stereoisomer mixture and the equivalent of the palm adjuvant.

The method described in Comparative Test Example 2 was carried out except that the R-isomer pair S- in N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide The ratio of isomers was set to 14:86 and different equivalents of the palmitic adjuvants shown in Table 5 below were used. The ratio of the isomers separated into solids was determined under the HPLC conditions of Comparative Test Example 2. Further, the reaction yield was calculated according to Mathematical Formula 2 below.

In addition, each of the N-[4-[(1R)-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide and N-[4-((1S)) After the ratio of 1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide, the ratio of the S-isomer and the ratio of the R-isomer contained in the mother liquor are in the comparative test examples. 2 was determined under HPLC conditions. The results are shown in Table 5. [table 5] [Table 6] [Table 7] * When L-type palmitic adjuvants are used, the R-isomers and S-isomer systems are obtained in reverse proportions, in Tables 5-7.

According to the results of Table 5, when the ratio of the R-isomer:S-isomer of the mixture of stereoisomers was 14:86, a higher ratio of the S-isomer than the results of Table 4 was obtained. .

Based on the 1 eq. of the stereoisomer mixture, when the palm adjuvant is used in an amount of 1 eq. or more, a higher ratio of S- can be obtained as compared with the mixture of stereoisomers before the reaction. isomer. Particularly when the palm adjuvant was used in an amount of 1.0 eq., the ratio of the S-isomer of the solid to the solid was 97% and the yield was 74%, which was the highest result.

Particularly when the palm adjuvant is used in an amount of 1.0 eq., the R-isomer remaining in the isomer mixture after precipitation as a solid S-isomer: S-isomer The ratio is controlled at 45:55, which means that substantially only the S-heterogeneous system is selectively separated.

Further, if it is shown in Table 6, wherein the ratio of the R-isomer:S-isomer in the mixture of stereoisomers is 25:75 and the ratio in Table 7 is 10:90, it can be obtained as compared with the table. 4 results in a higher proportion of the S-isomer.

In particular, when the palm adjuvant is used in an amount of 1 eq. per equivalent of the mixture of stereoisomers or above, a higher ratio of the S-isomer to the mixture of stereoisomers before the reaction can be obtained. . Particularly when the palmitic adjuvant was used in an amount of 1.0 eq., the S-isomer ratio of the separation to solid was 88% and 98% and the yield was 72% and 76%, which was the highest result. Further, as seen from Table 6, when the R:S ratio is 25:75 and the palmarity adjuvant is used in an amount of 1.2 eq, the R:S ratio remaining in the mother liquor after separating the solid isomer compound Controlled at 51:49.

Thus, according to the present disclosure, a relatively high proportion of the selective S-isomer can be resolved separately from a mixture of stereoisomers rich in S-isomers. Further, after the analysis, the ratio of the R-isomer:S-isomer contained in the mother liquor was about 1:1. Thus, a mixture of stereoisomers can be resolved into a racemate by removing the S-isomer separately.

Furthermore, the resolved S-isomer compound with high optical purity can be used to obtain the racemate of the stereoisomer compound via another racemization process.

Thus, the present disclosure uses a mixture of stereoisomers for racemization while minimizing the loss of the R-isomer. Furthermore, the obtained racemate can be used in another reaction.

In addition, the method minimizes the R-isomer loss caused by the racemization process and performs racemization by the S-isomer according to the disclosure, which is selected by separately analyzing the resolved S-isomer. Sexual racemization. Thus, according to the present disclosure, a high proportion of the S-isomer can be obtained from a mixture of stereoisomers in the presence of a polar aprotic solvent and the mother liquor can be converted into a racemic product such that it can be used again for palm Sexual analysis process.

Further, according to the present disclosure, the mother liquor remaining after obtaining the R-isomer compound using a polar aprotic solvent and a D-type palmarity adjuvant is recrystallized from aqueous ammonia to obtain a solid compound (R: S = 14: 86), which is then treated with the same D-type palm adjuvant to replace the solvent with a single polar aprotic solvent. In this method, the S-isomer can be selectively resolved to convert the mother liquor into a racemic product (R: S is about 1:1) so that it can be reused for palmar analysis and via elimination. Spin action to convert the resolved S-isomer to a racemic mixture (R: S = 1 : 1). This is a method that produces a racemic mixture while minimizing the loss of the R-isomer. Therefore, because the present method uses the same kind of palm adjuvant to resolve the R-isomer process, it exhibits high industrial applicability without causing cross-contamination by the opposite palm adjuvant. As a result, the R-isomer can be obtained via a replacement solvent, and the mother liquor containing the mixture of stereoisomers can be recovered by continuous palmitic analysis, and the mother liquor can be reintroduced to the palmar analysis after simple racemization. In short, the disclosed method exhibits cost-effective and environmentally friendly characteristics.

When an L-type palmitic adjuvant is used in the present methods and in the above tests, an R-stereoisomer corresponding to INT-3 can be obtained which can be used in other processes as described below. [Test Example 4] Preparation of (R)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-6) -trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl- Pyridin-3-yl)-acrylamide is based on the method described in Korean Patent Application No. 10-2009-7004333, using N-{4-[(1R)-1-aminoethyl]-2,6-difluoro Phenyl}methanesulfonamide obtained.

In particular, N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide HCl salt (62 mg, 0.22 mmol) and 3-(2-propane) Reaction of -6-trifluoromethyl-pyridin-3-yl)-acrylic acid (56 mg, 0.22 mmol). ¹ H NMR (300MHz, DMSO-d ₆ ): δ 9.50 (bs, 1H), 8.81 (d, 1H, J = 7.8 Hz), 8.16 (d, 1H, J = 8.4 Hz), 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 = 6.9 Hz), 0.92 (t, 3H, J = 7.2 Hz). ESI[M+H] ⁺ : 492

Therefore, the R-isomer of the compound represented by Chemical Formula 1 and analyzed by the present disclosure method can be used for the preparation of an intermediate which can be used as a novel compound for the action of a TRPV1 antagonist, which is based on Korean Patent Application No. 10-2009- The substance or method described in 7004333.

Claims (28)

A method for the palmar analysis of a mixture of stereoisomers, comprising mixing a mixture of a stereoisomer of a compound represented by Chemical Formula 1 with a palmitic adjuvant in the presence of a polar aprotic solvent, a non-Spiethy isomer salt of the compound represented by Chemical Formula 1 in which an excess of the Spiegelmer is precipitated by the palm adjuvant: [Chemical Formula 1] Wherein each of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ represents any one selected from the group consisting of H, —NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _a group consisting of _2-6 alkynyl and halogen, and R ₁ and R ₂ have different substituents. The method for interpreting a mixture of stereoisomers according to claim 1, wherein R ₂ is H, and the palm adjuvant is selected from the group consisting of 2,3-dibenyl tartaric acid a group consisting of O,O' -di- p -tolylcarbyl tartaric acid, its stereoisomers, and combinations thereof. The method for interpreting a mixture of stereoisomers according to claim 1, wherein when the palm adjuvant is selected from (+)-2,3-dibenridyl- An S-type optical isomerism system of the compound represented by Chemical Formula 1 when D-tartaric acid, (+)- O, O'-di- p -tolylmethyl-D-tartaric acid, and combinations thereof Obtained in excess by the mirror image isomer. The method of claim 1, wherein the palm adjuvant is selected from (-)-2,3-dibenyl-based- R-type optical isomerism system of the compound represented by Chemical Formula 1 when L-tartaric acid, (-)- O, O'-di- p -tolylmethyl-L-tartaric acid, and combinations thereof Obtained in excess by the mirror image isomer. The method of claim 1, wherein the halogen is at least one selected from the group consisting of F, Cl, Br, and I. The method for interpreting a mixture of stereoisomers according to claim 5, wherein any one of R ₁ is selected from the group consisting of methyl, ethyl, propyl, butyl and pentyl groups. and R ₂ based H. The method of claim 6, wherein R ₁ is a methyl group, R ₃ and R ₇ are each H, and R ₄ , R ₅ and R ₆ are each One selected from the group consisting of F, Cl, Br, I, and C _1-6 alkyl. The method of claim 7, wherein the R ₄ and R ₆ systems are each a F and an R ₅ -methyl group, and the compound is N-{4-[(1R). /S)-1-Aminoethyl]-2,6-difluorophenyl}methanesulfonamide. The method for interpreting a mixture of stereoisomers according to claim 1, wherein the polar aprotic solvent is at least one selected from the group consisting of ethyl acetate, tetrahydrofuran, acetonitrile, acetone, and combinations thereof. Group. 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 to dissolve the entire mixture. The method for interpreting a mixture of stereoisomers according to claim 11, wherein the polar aprotic solvent is 5-15 times (v/w) corresponding to the total weight of the mixture of stereoisomers. Add in quantity. The method for interpreting a mixture of stereoisomers according to claim 1, wherein the mixing step is carried out at 40 to 70 ° C at the boiling point of the solvent or by raising the temperature to the boiling point of the solvent mixture. The method for palmar parsing a mixture of stereoisomers according to any one of claims 1 to 13, wherein the equivalent ratio of the palm adjuvant is based on 1 mole equivalent of the mixture of stereoisomers 0.5-2.0 eq. The method of claim 14, wherein the equivalent ratio of the palm adjuvant is 0.8-1.5 eq based on 1 mole equivalent of the mixture of stereoisomers. The method of claim 14, wherein the R-isomer of the mixture of stereoisomers: the ratio of the S-isomer is 1: 9 to 9: 1 . The method of claim 16, wherein the R-isomer of the mixture of stereoisomers: the ratio of the S-isomer is 1: 3 to 1: 9 . The method for interpreting a mixture of stereoisomers as described in claim 14, wherein the step of precipitating the non-Spiegelmer salt of the compound represented by Chemical Formula 1 in excess of the mirror image isomer Thereafter, it further comprises a step of recovering the precipitated diastereomer salt and adjusting the R-isomer of the stereoisomer mixture contained in the mother liquor: the S-isomer ratio is 3:7 to 7 : 3. The method of claim 18, wherein the R-isomer comprising the mixture of stereoisomers in the mother liquor: the S-isomer ratio is adjusted to 4: 6 to 6: 4. A stereoisomer of a compound isolated and obtained from a mixture of stereoisomers by a method as defined in claim 14, wherein the stereoisomer has the following image isomer excess: 80% ee or more, 82% ee or above, 84% ee or above, 86% ee or above, 88% ee or above, 90% ee or above, 92% ee or above, 94% ee or above, 96 % ee or above, 97% ee or above, 98% ee or above, or 99% ee or above. A stereoisomer of claim 20 which is N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide or N-{4-[ (1S)-1-Aminoethyl]-2,6-difluorophenyl}methanesulfonamide. A method for producing a compound represented by the following Chemical Formula 3a or 3b, which comprises: palm-resolving a stereoisomer of a compound represented by Chemical Formula 1 using a method as defined in any one of Claims 1 to 13 a mixture; and converting the resolved stereoisomer to a compound represented by Chemical Formula 3a or 3b: [Chemical Formula 3a] [Chemical Formula 3b] Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ each represent one selected from the group consisting of H, —NH _{2 ,} C _1-6 alkyl, C _2-6 alkenyl, C _a group consisting of _2-6 alkynyl and halogen, and R ₁ and R ₂ have different substituents. The method of claim 22, wherein the compound of the formula 3a is (R)-N-[1-(3,5-difluoro-4-methylsulfonylamino-phenyl)-ethyl]- 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-propenylamine, and the compound represented by Chemical Formula 1 is N-{4-[(1R/S)-1- Aminoethyl]-2,6-difluorophenyl}methanesulfonamide. The method of claim 22, wherein the step of converting the resolved stereoisomer to the compound of formula 3a or 3b comprises coupling N-{4-[(1R)-1-aminoethyl]-2 , 6-difluorophenyl}methanesulfonamide (INT-3) and 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)acrylic acid (INT-7). (R)-N-[1-(3,5-Difluoro-4-methylsulfonylamino-phenyl)-ethyl]-3-(2-) obtained by the method defined in claim 22 Propyl-6-trifluoromethyl-pyridin-3-yl)-propenylamine having a mirror image of 96% or more, 97% or more, 98% or more, or 99% or more An excess of isomers. An optical resolution kit comprising: a palmarity adjuvant, which is at least one selected from the group consisting of 2,3-dibenzimidyl tartaric acid, O, O'-di- p -tolylmethyl tartaric acid, and a stereo a group consisting of isomers and combinations thereof; a polar aprotic solvent; and a manual for the use of the palm adjuvant. The optical resolution kit of claim 30, wherein the palm adjuvant is used in an amount of from 0.5 to 2.0 eq. per optical equivalent of the mixture of stereoisomers. The optical resolution kit of claim 30, wherein the manual for the palm adjuvant comprises a description of the method defined in claim 18.