TWI725098B - 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

A method for the palm analysis of N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives by using polar aprotic solvents

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

Recently, there has been an increasing demand for sterically pure compounds. One of the important uses of this pure stereoisomer is as a synthetic intermediate in the pharmaceutical field. For example, it has gradually been demonstrated that a single enantiomerically pure drug has many advantages over a racemic drug mixture. These advantages usually include less side effects and higher efficacy associated with the pure compounds of the enantiomers [see, Stinson, S.C., Chem Eng News, Sept. 28, 1992, pp. 46-79].

For example, triadimenol may have 4 types of isomers, among which the (-)-(1S,2R)-isomer has the (+)-(1R,2R)-isomer Higher activity, and (-)-(1S,2S)-isomer has higher activity than (+)-(1R,2S)-isomer. It is known that the (1R, 2R)-isomer of dichlorobutrazole has the highest activity among the four types of isomers of dichlorobutrazole. It is also known that the (+)-(2S,4S)- and (-)-(2S,4R)-isomers of etaconazole have a higher sterilizing effect than other etaconazole isomers. .

Therefore, if only one isomer with high activity can be selectively prepared, a small amount of isomer can be used to obtain a high degree of effect, and thus reduce environmental pollution caused by the use of chemicals. In particular, in the case of pharmaceuticals, when any isomer shows toxicity to the human body, it is very important to selectively prepare a single isomer.

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

For example, it is shown that N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives containing vanillin antagonist are effective if they are pure stereoisomers [see WO2008-013414 A1, WO2007 -133637 A2, WO2007-129188 A1, WO2010-010934 A1].

A known method for preparing the single isomer of the N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivative is an asymmetric synthesis method using Elman's adjuvant. For example, WO2008-013414 A1, WO2007-133637 A2, WO2007-129188 A1 and WO2010-010934 A1 disclose methods for preparing desired stereoisomers by introducing Elman adjuvants and using them to induce asymmetry reduction (reduction). However, the above methods need to maintain a low temperature to increase the excess of enantiomers (%ee), risk due to excess hydrogen and heat dissipation during the quenching of the reaction, and excessive organic and inorganic waste generated after the quenching of the reaction, which leads to processing Restrictions on procedures and costs. [References] [Patent Documents] WO2008-013414 A1 WO2007-133637 A2 WO2007-129188 A1 WO2010-010934 A1

[Technical problem] Although the asymmetric synthesis of N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives Law has been reported so far, because of cost-effectiveness and safety, no commercially viable method has been established. Therefore, in consideration of cost-effectiveness and processing safety, the technical problem to be solved by the present disclosure is to provide a novel method for the palm analysis of stereoisomer mixtures using polar aprotic solvents.

[Technical Solution] In a general aspect, it provides a compound with N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivative salt and a high optical activity Auxiliary agent, a method to resolve the N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivative represented by the following chemical formula 1 into individual compounds with high optical purity. [Chemical formula 1]

More specifically, it provides a method for analyzing N-[4-(1-amino group) with high optical purity by (R,S)-N-[4-(1-aminoethyl)-phenyl]-sulfonamide analysis. Ethyl)-phenyl]-sulfonamide method, the method comprises: making (R,S)-N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivative and one The optically active palm auxiliary agent is mixed to form (R)- or (S)-type optically active N-[4-(1-aminoethyl)-phenyl]-sulfonamide diacyl tartrate or its solvent Compound, and separate the optically active N-[4-(1-aminoethyl)-phenyl]-sulfonamide salt or solvate with a base to obtain optically active N-[4-(1-amine Ethyl)-phenyl]-sulfonamide.

According to this method, N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives can be easily resolved into individual compounds with high optical purity.

N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide (N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide) series The general name of the compound represented by the following chemical formula 2 and is known to be useful in the preparation of TRPV1 (transient receptor potential cation channel subfamily V member 1), or capsaicin receptor ( capsaicin receptor), vanilloid receptor 1 (vanilloid receptor 1) antagonist compound intermediate. [Chemical formula 2]

As shown in chemical formula 2, N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide is a handheld compound, wherein the carbon atom bound to the amino group is As the palm center.

[Advantageous effect] 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 binding to an amine group) can be easily resolved into Individual compounds with high optical purity. Compared with the asymmetric synthesis method using Elman adjuvants, this method provides improved safety and cost-effectiveness. It performs palm analysis to at least the same optical purity as that of the asymmetric synthesis method, and is recovered and reused. Salts exhibit high cost-effectiveness and environmental friendliness. Therefore, the method can be used to prepare starting materials for compounds that require palm analysis in the fields of pharmaceuticals and cosmetics.

In particular, compared to the conventional asymmetric synthesis method of Elman adjuvant, this method provides higher efficiency according to one aspect of the disclosure, and therefore provides the desired stereoisomer at least equal to the optical purity of the conventional method, and Shows high efficiency and high cost-effectiveness in mass production.

In addition, according to the method of the present disclosure, the mother liquor of the stereoisomer mixture can be controlled or converted into a racemate, which contains the S-isomer and R-isomer in a ratio of about 1:1. It is also possible to perform racemization to high purity only by the palm analysis of the stereoisomer compound without using any additional racemization reaction. Therefore, the method according to the present disclosure does not require any additional methods to directly use the mother liquor in another palm analysis step. As a result, unlike the conventional racemization reaction, it can provide high cost-effectiveness without loss of compound.

In one aspect, there is provided a method for the palm analysis of a mixture of stereoisomers, which includes mixing a mixture of stereoisomers of a compound with a palm auxiliary agent in the presence of a solvent, and the isomerization is The diastereomer salt of the compound is precipitated with the palmar auxiliary agent in excess volume.

According to a specific embodiment, the palm assisting agent can be at least one selected from 2,3-dibenzoyl tartaric acid, O, O'-di- p -toluene Tartaric acid ( O, O'-di-p-toluoyl tartaric acid), its stereoisomers and combinations thereof.

As used herein, the term "enantiomeric excess" generally means an increase in the proportion of any enantiomeric isomers, and therefore not only means an excess of one enantiomeric isomer compared to a racemic mixture but also Any enantiomers of other mixtures with a ratio different from 1:1 enantiomers increase (the same ratio is a racemic mixture). According to a specific embodiment, "an Spiegelmer excess" can correspond to the following Spiegelmer excess (%ee): 80% or more, 82% or more, 84% or more, 86% or more Above, 88% or above, 90% or above, 92% or above, 94% or above, 95% or above, 96% or above, 97% or above, 98% or above, Or 99% or more. Similarly, the term "high optical purity" used herein is well known to those skilled in the art. According to a specific embodiment, the term "high optical purity" can correspond to the following enantiomer excess: 80% or more, 82% or more, 84% or more, 86% or more, 88% or Above, 90% or above, 92% or above, 94% or above, 95% or above, 96% or above, 97% or above, 98% or above, or 99% or above the above.

The chiral auxiliary used herein is well known to those skilled in the art. In particular, the palm auxiliary agent refers to a compound that is temporarily incorporated into the synthesis process of an organic compound to control the stereochemical result of the synthesis of the organic compound. This chiral auxiliary can be used as an auxiliary to determine at least one stereoselectivity of a series of reactions (see the page of chiral auxiliary in Wikipedia, http://en.wikipedia.org/wiki/ Chiral_auxiliary) . The "palm adjuvant" used in this article is interchangeable with "palm acid".

According to another specific embodiment, the 2,3-dibenzoyl tartaric acid may be (+)-2,3-dibenzoyl-D-tartaric acid ((+)-2,3-dibenzoyl-D-tartaric acid) or (-)-2,3-dibenzoyl-L-tartaric acid ((-)-2,3-dibenzoyl-L-tartaric acid), which are optical isomers of each other. In addition, O,O' -di- p -tolyl tartaric acid may be (+)- O, O'-di- p -tolyl-D-tartaric acid ((+)- O,O' -di - p -toluoyl-D-tartaric acid ) or (-) - O, O ' - two - p - toluyl acyl -L- tartaric acid ((-) - O, O ' -di- p -toluoyl-L- tartaric acid), which are optical isomers of each other. In the case of these tartaric acid derivatives, the D-isomer and the L-isomer can be used alone or in combination. However, each isomer can preferably be used alone. When the method of the present disclosure combines the D- and L-optical isomers of tartaric acid derivatives, the optical purity may be reduced compared to the optical purity obtained when each D- and L-isomer is used alone.

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

According to yet another specific embodiment, the method may be a method for obtaining R-type or S-type optical isomers, which has a mixture of stereoisomers with high optical purity.

According to still another specific embodiment, when the palm assisting agent is selected from (+)-2,3-dibenzyl-D-tartaric acid, (+)- O,O' -di- p- For any of the group consisting of tolyl-D-tartaric acid and combinations thereof, this method may be a method for obtaining the S-type optical isomer of the compound in an excess of the mirror isomer.

According to yet another specific embodiment, when the palm assisting agent is selected from (-)-2,3-dibenzyl-L-tartaric acid, (-)- O,O' -di- p- Tolyl-L-tartaric acid and any of the group consisting of combinations thereof, this method may be used to obtain R-type optical isomers of the compound in an excess of mirror isomers.

其中各R₁ 、R₂ 、R₃ 、R₄ 、R₅ 、R₆ 及R₇ 代表任一選自於由H、-NH₂ 、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基及鹵素所組成之群組，且 R₁ 及R₂ 具有不同取代基。According to yet another specific embodiment, the compound may be represented by Chemical Formula 1. [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 H, -NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _The 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 yet another specific embodiment, R ₁ can be any selected from the group consisting of methyl, ethyl, propyl, butyl and pentyl, and R ₂ can be H.

According to yet another specific 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 any one selected from F, Cl, Br, I And C _1-6 alkyl group.

According to yet another specific embodiment, each of R ₄ and R ₆ may be F, and R ₅ may be a methyl group.

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

According to yet another specific embodiment, the solvent may be a polar aprotic solvent.

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

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

According to yet another embodiment of the method, the mixing step 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 yet another specific embodiment, the mixing step can be performed by increasing the temperature while stirring for 1-4 hours.

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

According to yet another specific 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 40-60°C, more particularly 45-55°C, and even more particularly 50°C.

According to yet another specific embodiment, the agitation may be performed for at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours or at least 5 hours, or at most 6 hours, at most 5 hours, at most 4 hours, at most 3 hours, at most 2 hours or at most 1 hour. In particular, the agitation may be performed for 2-4 hours, more particularly 2.5-3.5 hours, and even more particularly 3 hours.

According to yet another specific embodiment, the palm auxiliary agent is used in an amount of 0.5-2.0 equivalents per equivalent of the stereoisomer mixture, especially 0.8-1.5 equivalents.

According to yet another specific embodiment, the palm auxiliary agent is used in the following amounts based on 1 mol 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., at most 1.5 eq., at most 1.4 eq., at most 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 yet another specific embodiment, the mixture of stereoisomers may have a ratio of R-isomer: S-isomer of 1:9 to 9:1, which includes any ratio between 1:9 and 9:1. Integer ratio. In particular, according to yet another specific embodiment, the stereoisomer mixture may have the following R-isomer: S-isomer ratio: 1: 9 or less, 1: 8 or less, 1: 7 Or below, 1: 6 or below, 1: 5 or below, 1: 4 or below, 1: 3 or below, 1: 2 or below, 1: 1 or below, 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 More than or 1: 9 or more.

According to yet another specific embodiment, after the step of precipitating the diastereomer salt of the compound in excess of the spiegelmer [Chemical Formula 1] with a palm auxiliary agent, the method may further include the following step: recovering the The precipitated diastereomer salt and the R-isomer: S-isomer ratio of the stereoisomer mixture contained in the mother liquor is adjusted to 3: 7 to 7: 3. In particular, according to yet another specific embodiment, the step of adjusting the ratio of R-isomer: S-isomer can be performed by adjusting the ratio to the following: 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 separated and obtained from a mixture of stereoisomers according to the method of the present disclosure, wherein the stereoisomer has the following mirror 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 specific 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, which combines four different atoms, atomic groups or functional groups. If it is a compound with asymmetric carbon atoms, it has optical rotatability, optical activity, or optical isomers.

The term "stereoisomer mixture" as used herein refers to a mixture of two optically active isomer compounds that are enantiomers, where the mixture may have a mixture ratio of 1:1 (corresponding to a racemic mixture), or A ratio of integers between 1:10 and 10:1. According to another specific embodiment, the mixture of stereoisomers may be artificially synthesized or may be a mixture having an unknown ratio of R-optical isomer to S-optical isomer. 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, regardless of the mixing ratio, the desired type of optical isomer with high optical purity can be obtained.

As used herein, N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide means a compound designated as CAS number 1202743-51-8, which has a molecular weight of 250.27 Da, and can be used interchangeably with INT-2 in the following. It may be a mixture of stereoisomers, which contains R-isomer and S-isomer mixed with each other.

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 number 956901-23-8 and has a molecular weight of 286.73 Da, and N-{4-[(1R)-1 -Aminoethyl]-2,6-difluorophenyl}-methanesulfonamide forms one corresponding to CAS number 957103-01-4. In addition, as used herein, it is used interchangeably with the R-isomer of INT-3 below.

According to yet another specific 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 yet another specific embodiment, (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) (PAC-14028) corresponds to CAS number 1005168-10-4 and has a molecular weight of 491.47 Da.

In yet another aspect, the R- or S-isomer of INT-3 is obtained by a method comprising the following steps: Make INT-2 (N-[4-(1-aminoethyl)-2 ,6-Difluorophenyl]-methanesulfonamide) is mixed with a palm-like adjuvant; a polar aprotic solvent is added to the resulting mixture, which corresponds to 10 times the weight of INT-2 (v/w) Agitate the mixed solution at 30-70°C under reflux for 1-4 hours, which contains the polar aprotic solvent added to it; cool the agitated mixture; and filter the obtained by the cooling step Solid to obtain INT-3 chiral acid salt.

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

According to another specific embodiment, the cooling step can be performed by cooling the mixture to the following temperature: 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 yet another specific embodiment, the method may further comprise the step of separating the palmic acid from the generated INT-3 palmic acid salt. In particular, the separation step can be carried out by the following method: introducing 5 times the weight of the salt to the INT-3 palm acid salt and 2 eq. of 28 vol% ammonia; stirring the obtained suspension for 20 -Filtrate for 50 minutes; and remove the residual water under reduced pressure to obtain the R- or S-isomer of INT-3.

In yet another aspect, there is provided a method for the palm analysis of a mixture of stereoisomers, which comprises the following steps: (1) Mixing a mixture of stereoisomers of a compound with a palm auxiliary agent, the compound It has an asymmetric carbon atom bonded to the amine group.

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

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

According to yet another specific embodiment, the method may further include step (2) after step (1): adding a solvent to the mixture of step (1).

According to yet another specific embodiment, the solvent may be a polar aprotic solvent.

According to yet another specific embodiment, the method may further include step (3), agitating the mixed solution in reflux, which contains the solvent added thereto.

According to yet another specific embodiment, the agitation of step (3) can be performed: 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 specific embodiment, the agitation in step (3) can be performed 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 yet another specific embodiment, the method may further include step (4): cooling the mixture of step (3).

According to yet another specific embodiment, the method may further include step (5): filtering the solid formed by cooling to obtain the diastereomer salt of the compound. In particular, according to yet another specific embodiment, the diastereomer salt of the compound may be an INT-3 diastereomer salt.

According to yet another specific embodiment, the method may further include step (6): removing or separating the palmitic acid from the generated diastereomer salt.

According to yet another specific embodiment, step (6) may include step 1): introducing water and ammonia into the INT-3 diastereomer salt. In particular, according to yet another specific embodiment, in step (6), the water system is used in the following amount based on the weight of the INT-3 diastereomer salt: at least 2 times, at least 3 times, at least 4 times, at least 5 times Times, at least 6 times or at least 7 times, or at most 7 times, at most 6 times, at most 5 times, at most 4 times, at most 3 times, or at most 2 times. In particular, according to another specific embodiment of the present disclosure, in step (6), the ammonia water can be an aqueous solution of the following proportions 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 at most 40 vol%, at most 36 vol%, at most 32 vol%, at most 28 vol%, at most 24 vol% or at most 20 vol%. In particular, according to another specific embodiment of the present disclosure, in step (6), the ammonia water is introduced in the following amounts: 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 at most 4 eq., at most 3.5 eq., at most 3 eq., at most 2.5 eq., at most 2 eq., at most 1.5 eq., at most 1 eq. or at most 0.5 eq..

According to yet another specific embodiment, step (6) may further include step 2) after step 1): agitating the mixed solution. In particular, according to yet another specific embodiment, the agitation in step (6) is performed: 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 yet another specific embodiment, step (6) may further include step 3): filtering the suspension obtained by stirring.

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

[化學式3b]

其中各R₁ 、R₂ 、R₃ 、R₄ 、R₅ 、R₆ 及R₇ 代表任一選自於由H、-NH₂ 、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基及鹵素所組成之群組，且R₁ 及R₂ 具有不同取代基。該轉換步驟係於韓國專利申請號10-2009-7004333中被描述。In yet another aspect, a method for preparing a compound represented by the following chemical formula 3a or 3b is provided, which comprises: using the method of the present disclosure to analyze a mixture of stereoisomers of a compound [chemical formula 1] Show; and convert the resolved stereoisomer into a compound shown in Chemical Formula 3a or 3b: [Chemical Formula 3a]

[Chemical formula 3b]

Wherein each of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ represents any one selected from H, -NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _The 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 represented by formula 3a can be (R)-N-[1-(3,5-difluoro-4-methylsulfonylamino-phenyl)-ethyl]-3 -(2-Propyl-6-trifluoromethyl-pyridin-3-yl)-propenamide (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 into a compound represented by formula 3a or 3b can be achieved 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 stereoisomer of 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 combining the stereoisomer with the definition therein The material reaction. Therefore, in yet another aspect, there is provided a method for preparing the novel drug disclosed in Korean Patent Application No. 10-2009-7004333 using the analyzed stereoisomers of the method disclosed in the present disclosure, or the novel drug obtained therefrom.

In yet another aspect, there is provided (R)- which is obtained by the method of the present disclosure and has an excess of 96% or more, 97% or more, 98% or more, or 99% or more of the enantiomer N-[1-(3,5-Difluoro-4-methylsulfonylamino-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridine-3-基)-acrylamide.

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

In yet another aspect, a pharmaceutical composition is provided, which comprises (R)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)- of the present disclosure Ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-propenamide, its optical isomers or its pharmaceutically acceptable salts and pharmaceutically acceptable A vector used to prevent or treat diseases related to pathological stimulation and/or abnormal expression of vanilloid receptors, which is selected from the group consisting of pain, joint inflammatory diseases, HIV-related nerves Diseases, nerve damage, neurodegeneration, stroke, urinary incontinence, cystitis, gastroduodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency (fecal urgency), gastroesophageal reflux (GERD), clone Pulmonary disease, asthma, chronic obstructive pulmonary disease, cough, atopic/allergic/inflammatory skin disease, psoriasis, itching, prurigo, skin irritation, inflammation of the eyes or mucous membranes, misophonia, tinnitus, vestibular allergy Reactions, 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 nerve pain, postoperative pain, tooth pain, Fibromyalgia, myofascial pain syndrome, lower back pain, migraine and other types of headaches or pain related to the disease.

In yet another aspect, an optical analysis kit is provided, which includes: a palm auxiliary agent; a polar aprotic solvent; and a manual auxiliary agent manual.

According to a specific embodiment, the palm assisting agent may be at least one selected from 2,3-dibenzyltartaric acid, O, O'-di- p -tolyltartaric acid, and its stereoisomers The group composed of and its combination.

According to another specific embodiment, the palm auxiliary agent is used in an amount of 0.5-2.0 eq. per molar equivalent of the stereoisomer mixture subjected to optical analysis.

According to yet another specific embodiment, the salt-forming adjuvant compound is used in an amount of 0.8-1.5 eq. per molar equivalent of the stereoisomer mixture subjected to optical analysis.

According to yet another specific embodiment, the user manual contains the following content: when using the optical resolver, for every molar equivalent of the stereoisomer mixture subjected to optical resolution, the use amount of the palm auxiliary agent is 0.5-2.0 eq. ( Especially 0.8-1.5 eq.).

According to yet another specific embodiment, the user manual may include the following content: when the palm auxiliary agent is used, the palm auxiliary agent is mixed with the stereoisomer mixture in the presence of a polar aprotic solvent.

According to yet another specific embodiment, the user manual may include content related to the palm analysis method for the stereoisomer mixture used in the present disclosure.

[Invention Implementation Mode] Examples and test examples will now be described more fully hereinafter. The following examples and test examples are only for illustrative purposes and the scope of the disclosure should not be construed as being limited to the illustrative specific examples listed therein. In addition, those skilled in the art will understand that various changes in form and details can be made without departing from the scope of disclosure as defined in the appended patent scope. [Comparative Test Example 1] Determine the optical purity of the conventional asymmetric synthesis process

According to the following reaction framework 1, a conventional asymmetric synthesis process is performed. [Response Architecture 1]

N-{2,6-Difluoro-4-[1-(2-methyl-prop-2-sulfynylimino)-ethyl]-phenyl}-methanesulfonamide (1 eq.) was added to and dissolved in tetrahydrofuran (THF, 20 mL) in an amount corresponding to 10 times its weight. Secondly, NaBH ₄ (4 eq.) was further dissolved in the resulting solution, and then reacted at the temperature listed in Table 1 below for 10 hours. Then, CH ₃ OH was added dropwise until no more hydrogen escaped.

After the resulting mixture was concentrated under reduced pressure, it was purified by chromatography to obtain N-{2,6-difluoro-4-[1-(2-methyl-prop-2-sulfonyl) Amino)-ethyl]-phenyl}-methanesulfonamide (N-{2,6-difluoro-4-[1-(2-methyl-propan-2sulfynylamino)-ethyl]-phenyl}-methanesulfonamide). After adding an excess of 4M HCl in dioxane to it dropwise, the resulting mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue remaining after preparation is purified by recrystallization with 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 have an excess of spiegelmer by the same process 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 96% or higher optical activity, as shown in Table 1. On the contrary, according to the present disclosure, the same degree of optical activity can be obtained only by a process involving agitation and purification with a solvent at a temperature of 50°C. Therefore, it can be seen that compared with the conventional method, the disclosed method is significantly more cost-effective. In addition, when the reaction is extended to an industrial plant unit, it is easier to control the temperature at 50°C for 10 hours compared to -40°C. As a result, compared with the conventional method, the disclosed method is more suitable for expanding the scale of the reaction.

In addition, if it is a conventional method, 2-4 eq. of sodium borohydride is used, so an excessive amount of explosive hydrogen will be generated during the quenching of the reaction, causing heat loss. This corresponds to a process that involves extremely dangerous reactions. On the contrary, the present disclosure provides the unique effect of producing commercially usable optically active isomers without including dangerous processes such as excessive generation of explosive hydrogen gas or heat loss.

Therefore, it can be seen from the above results that, compared with the conventional method, the content of this disclosure corresponds to a method involving a more cost-effective and safe manufacturing process. [Comparative Test Example 2] Type analysis and determination of optical purity when polar protic solvents are used for analysis

According to the method described in Bioorganic & Medicinal Chemistry (15 (18), 6043-6053; 2007), N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide (Mixture of R-isomer and S-isomer, R: S = 1: 1) is prepared. Mix the obtained N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide system in a ratio of 1 eq.: 1eq with the optical components listed in Table 2 below. Resolving agent (Sigma-Aldrich). Then, a solvent (different polar protic solvents in Table 2 below) is 10 times the weight of N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide Is added to the resulting mixture. The mixed solution to which the solvent is added is refluxed 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 generated N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide palm acid salt, introduce 5 times the weight of the salt and 2 eq of water .Of 28 vol% ammonia water. Next, the reaction mixture was stirred for 30 minutes to provide a suspension, which was filtered through a Buchner funnel. Then, the remaining water was removed under reduced pressure and vacuum to obtain each of N-[4-((1R)-1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide and N- [4-((1S)-1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide.

A palm HPLC column (Shiseido Chiral CD-Ph) 4.6 mm x 250 mm, 5 μm) was used to analyze the optical purity (spiegelmer excess) of the produced INT-3. As the mobile phase, a mixed solution of 0.5 mol/L sodium perchlorate and methanol (75 vol%: 25 vol%) is used. The ratio of the palm acidic salts separated into solids was determined using Waters 32695 Alliance HPLC under the following conditions. Based on the ratio of each salt, the spiegelmer excess (ee%) of each salt can be calculated according to the following mathematical formula 1.

* 當使用L-類型掌性輔助劑，R-異構體及S-異構體係以相反比例獲得。The results of each salt ratio 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-spiegelmer%), 18.9 (S -Spiegelmer%) [Mathematical formula 1] Spiegelmer excess (% ee) = [(desired isomer)-(anti-isomer)]/ [(desired isomer) + (Trans-isomer)] x 100 [table 2]

* When using L-type palm auxiliaries, R-isomer and S-isomer system are obtained in opposite proportions.

From the above results, it can be seen that when using a polar protic solvent which is not the method disclosed in the present disclosure, a D-type palm auxiliary agent is used to resolve and obtain the R-isomer. In addition, 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 S-isomer system are obtained in the same ratio. Therefore, it can be seen that when solvent mixtures with different properties are used, it is impossible to analyze stereoisomer mixtures. [Test Example 1] Confirmation of analysis when using polar aprotic solvent for analysis

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

It can be seen from the above results that when a D-type palm adjuvant and a stereoisomer mixture are reacted in the presence of the polar aprotic solvent with the disclosed method, a higher ratio can be obtained in most polar aprotic solvents. S-stereoisomer. If it is dimethylformamide and dimethyl sulfide, N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide palmic acid salt is The solvent is completely dissolved and will not separate into solids. Therefore, it is impossible to determine whether the salt is resolved.

Among the polar aprotic solvents, acetone provides the highest yield of S-isomer. Therefore, the equivalent weight of the palm auxiliary agent is adjusted and the ratio of R-isomer:S-isomer in the mixture of stereoisomers is also adjusted in the presence of acetone as described below to determine the difference produced. The ratio and yield of the structure compound. [Test Example 2] When acetone solvent is used, the ratio and output are determined according to the equivalent of palm auxiliary agent

*  當使用L-類型掌性輔助劑，R-異構體及S-異構體係以相反比例獲得。The method described in Comparative Test Example 2 was carried out, except that acetone was used as a solvent and palm adjuvants of different equivalents were used in the manner shown in Table 4 below. The ratio of each isomer separated into solids was determined under the HPLC conditions of Comparative Test Example 2. In addition, the reaction yield is calculated according to Mathematical Formula 2 below. The results are shown in Table 4. [Mathematical formula 2] Yield (%) = (actual amount/theoretical amount) x 100 actual amount: the actual amount of product obtained theoretical amount: the maximum amount of product that can be obtained from a specific amount of reactant [Table 4]

* When using L-type palm auxiliaries, R-isomer and S-isomer system are obtained in opposite proportions.

It can be seen from the above results that solid isomers in different proportions and yields can be obtained according to the equivalent weight of the stereoisomer mixture and the palm auxiliary agent. When the equivalent of the palm adjuvant per equivalent of the stereoisomer mixture is 1 eq. or more, the analysis of the S-isomer is performed and when the palm adjuvant is used in the amount of 1.2 eq. S- The ratio of isomers is the highest. In addition, if the S-isomer is analyzed, the yield of the S-isomer is the highest when the palm auxiliary agent is used in an amount of 1.2 eq. [Test Example 3] Determine the optical purity and yield based on the R: S ratio of the stereoisomer mixture and the equivalent of the palm auxiliary agent

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

[表6]

[表7]

* 當使用L-類型掌性輔助劑，R-異構體及S-異構體係以相反比例獲得，在表5-7。In addition, each N-[4-[(1R)-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide and N-[4-((1S) After -1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide, the ratio of the S-isomer and the ratio of R-isomer contained in the mother liquor are in the comparative test example 2 Measured under HPLC conditions. The results are shown in Table 5. [table 5]

[Table 6]

[Table 7]

* When using L-type palm auxiliaries, R-isomer and S-isomer system are obtained in opposite proportions, as shown in Table 5-7.

According to the results in Table 5, when the ratio of R-isomer: S-isomer of the stereoisomer mixture is 14:86, a higher ratio of S-isomer can be obtained compared to the results in Table 4 .

Based on 1 eq. of the stereoisomer mixture, when the palm auxiliary agent is used in an amount of 1 eq. or more, a higher ratio of S- can be obtained compared to the stereoisomer mixture before the reaction. isomer. Especially when the palm assist agent is used in an amount of 1.0 eq., the ratio of the S-isomer separated into solid is 97% and its yield is 74%, which is the highest result.

Especially when the palm auxiliary agent is used in an amount of 1.0 eq., the R-isomer: S-isomer in the isomer mixture remaining in the mother liquor after the solid S-isomer is recovered The ratio is controlled at 45:55, which means that essentially only the S-isomer system is selectively separated.

In addition, if the ratio of R-isomer: S-isomer in the mixture of stereoisomers in Table 6 is 25: 75 and the ratio in Table 7 is 10: 90, you can obtain a comparison with Table 6 4 The result is a higher proportion of S-isomer.

In particular, when the palm auxiliary agent is used in an amount of 1 eq. or more per equivalent of the stereoisomer mixture, a higher proportion of S-isomer can be obtained compared to the stereoisomer mixture before the reaction. . Especially when the palm assist agent is used in an amount of 1.0 eq., the proportion of the S-isomer separated as solid is 88% and 98%, and the yield is 72% and 76%, which is the highest result. In addition, it can be seen from Table 6 that when the R:S ratio is 25:75 and the palm auxiliary agent is used in an amount of 1.2 eq, the R:S ratio remaining in the mother liquor after separating the solid isomer compound Was controlled at 51:49.

Therefore, according to the disclosed method, a higher ratio of selective S-isomer can be resolved separately from a mixture of stereoisomers rich in S-isomer. In addition, after the analysis, the ratio of the R-isomer:S-isomer contained in the mother liquor is approximately 1:1. Therefore, it is possible to resolve a mixture of stereoisomers into racemates by removing the S-isomer alone.

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

Therefore, the disclosed method uses a mixture of stereoisomers to perform racemization while minimizing the loss of R-isomer. In addition, the obtained racemate can be used in another reaction.

In addition, this method minimizes the loss of R-isomer caused by the racemization process according to the present disclosure and performs racemization from the S-isomer, which is achieved by individually selecting the resolved S-isomer Sexual racemization. Therefore, according to the disclosed method, a high proportion of 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 so that it can be reused in palm. Sexual analysis process.

In addition, according to the disclosed method, the mother liquor remaining after obtaining the R-isomer compound using a polar aprotic solvent and D-type palmar auxiliary agent is recrystallized with ammonia water to obtain a solid compound (R: S = 14: 86), which was then treated with the same D-type palm adjuvant and replaced the solvent with a polar aprotic solvent alone. In this method, the S-isomer can be selectively analyzed to convert the mother liquor into a racemic product (R: S is approximately 1: 1) so that it can be used again for palm analysis and via elimination. Rotation to convert the resolved S-isomer into a racemic mixture (R: S = 1: 1). This is a way to produce a racemic mixture while minimizing the loss of R-isomer. Therefore, because the disclosed method uses the same type of palm auxiliary agent in the process of analyzing the R-isomer, it shows high industrial applicability without causing cross-contamination by the opposite palm auxiliary agent. As a result, the R-isomer can be obtained by replacing the solvent, the mother liquid containing the stereoisomer mixture after continuous palm analysis can be recovered, and the mother liquid can be introduced again to the palm analysis after simple racemization. In short, the disclosed method shows high cost-effectiveness and environmental protection characteristics.

When an L-type palm adjuvant is used in the disclosed method and the above test, the R-stereoisomer corresponding to INT-3 can be obtained, which can be used in other processes described below. [Test Example 4] Preparation of (R)-N-[1-(3,5-difluoro-4-methylsulfonylamino-phenyl)-ethyl]-3-(2-propyl-6 -Trifluoromethyl-pyridin-3-yl)-acrylamide

(R)-N-[1-(3,5-Difluoro-4-methylsulfonylamino-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 was obtained.

In particular, N-{4-[(1R)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide HCl salt (62 mg, 0.22 mmol) and 3-(2-propane The reaction of 6-trifluoromethyl-pyridin-3-yl)-acrylic acid (56 mg, 0.22 mmol) and the resulting product was purified by crystallization with ether to obtain the title compound (81 mg, 73%). 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-isomer of the compound shown in Chemical Formula 1 and analyzed by the disclosed method can be used to prepare intermediates required for various novel compounds that can act as TRPV1 antagonists. It is based on Korean Patent Application No. 10-2009- The substance or method described in 7004333.

Claims (24)

A method for the palm analysis of a mixture of stereoisomers, which includes mixing a mixture of stereoisomers of the compound represented by chemical formula 1 with a palm auxiliary agent in the presence of a polar aprotic solvent One of the diastereoisomeric salts of the compound represented by the chemical formula 1 which is precipitated with the palm-like adjuvant in an excess of spiegelmer:

Wherein each of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ represents any one selected from H, -NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _The group consisting of 2-6 alkynyl and halogen, and R ₁ and R ₂ have different substituents; wherein, the polar aprotic solvent is at least one selected from ethyl acetate, tetrahydrofuran, acetonitrile, acetone, and A group formed by a combination. The method for palm analysis of a mixture of stereoisomers according to claim 1, wherein R ₂ is H, and the palm auxiliary agent is any one selected from 2,3-dibenzyl tartaric acid , O,O' -di- p -tolyl tartaric acid, its stereoisomers and combinations thereof. The method for palm analysis of a mixture of stereoisomers as described in claim 1, wherein, when the palm auxiliary agent is any one selected from (+)-2,3-dibenzyl- When D-tartaric acid, (+)- O, O'-di- p -tolyl-D-tartaric acid and the combination thereof form the group, the S-type optical isomer system of the compound represented by chemical formula 1 Obtained in excess of spiegelmer. The method for palm analysis of a mixture of stereoisomers as described in claim 1, wherein, when the palm auxiliary agent is any one selected from (-)-2,3-dibenzyl- When L-tartaric acid, (-)- O, O'-di- p -tolyl-L-tartaric acid and the combination thereof form the group, the R-type optical isomer system of the compound represented by chemical formula 1 Obtained in excess of spiegelmer. The method for the palm analysis of a mixture of stereoisomers as described in claim 1, wherein at least one halogen is selected from the group consisting of F, Cl, Br, and I. The method for the palm analysis of a mixture of stereoisomers as described in claim 5, wherein R ₁ is any one selected from the group consisting of methyl, ethyl, propyl, butyl and pentyl , And R ₂ is H. The method for the palm analysis of a mixture of stereoisomers as described in 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 is selected from the group consisting of F, Cl, Br, I and C _1-6 alkyl. The method for the palm analysis of a mixture of stereoisomers as described in claim 7, wherein R ₄ and R ₆ are each F and R ₅ are methyl groups, and the compound is N-{4-[(1R /S)-1-Aminoethyl]-2,6-difluorophenyl}methanesulfonamide. The method for the palm analysis of a mixture of stereoisomers as described in claim 1, wherein the polar aprotic solvent is acetone. The method for the palm analysis of a mixture of stereoisomers as described in claim 1, wherein the polar aprotic solvent is added in an amount capable of dissolving the entire mixture. The method for the palm analysis of a mixture of stereoisomers according to claim 10, wherein the polar aprotic solvent is 5-15 times (v/w) of the total weight of the mixture of stereoisomers The amount is added. The method for the palm analysis of a mixture of stereoisomers according to claim 1, wherein the mixing step is performed at 40-70°C at the boiling point of the solvent or raising the temperature to the boiling point of the solvent mixture. The method for the palm analysis of a mixture of stereoisomers according to any one of claims 1 to 12, wherein based on 1 mole equivalent of the mixture of stereoisomers, the equivalent ratio of the palm auxiliary agent is 0.5 -2.0eq. The method for the palm analysis of a mixture of stereoisomers as described in claim 13, wherein based on 1 mole equivalent of the mixture of stereoisomers, the equivalent ratio of the palm auxiliary agent is 0.8-1.5eq. The method for the palm analysis of a mixture of stereoisomers as described in claim 13, wherein the ratio of R-isomer:S-isomer of the stereoisomer mixture is 1:9 to 9:1 . The method for the palm analysis of a mixture of stereoisomers as described in claim 15, wherein the ratio of R-isomer:S-isomer of the mixture of stereoisomers is 1:3 to 1:9 . The method for the palm analysis of a mixture of stereoisomers as described in claim 13, in the step of precipitating the diastereomer salt of the compound represented by chemical formula 1 with the palmity adjuvant in excess of spiegelmers After that, it further includes a step of recovering the precipitated diastereomer salt and adjusting the ratio of R-isomer:S-isomer of the stereoisomer mixture contained in the mother liquor from 3:7 to 7:3. The method for the palm analysis of a mixture of stereoisomers as described in claim 17, wherein the R-isomer:S-isomer ratio of the stereoisomer mixture contained in the mother liquor is adjusted to 4:6 to 6:4. A method for preparing a compound represented by the following chemical formula 3a or 3b, which comprises: using a method as defined in any one of claims 1 to 12 to analyze the stereoisomers of a compound represented by chemical formula 1 Mixture; and converting the resolved stereoisomer into a compound represented by Chemical Formula 3a or 3b: [Chemical Formula 3a]

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ each represent any one selected from H, -NH _2, C _1-6 alkyl, C _2-6 alkenyl, C _The group consisting of 2-6 alkynyl and halogen, and R ₁ and R ₂ have different substituents. Such as the method of claim 19, wherein the compound represented by the chemical formula 3a is (R)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]- 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-propenamide, and the compound shown in formula 1 is N-{4-[(1R/S)-1- Aminoethyl]-2,6-difluorophenyl}methanesulfonamide. The method of claim 19, wherein the step of converting the resolved stereoisomer into a compound represented by formula 3a or 3b includes 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). An optical analysis kit, comprising: a palm-like auxiliary agent, which is at least one selected from the group consisting of 2,3-dibenzyltartaric acid, O, O'-di- p -tolyltartaric acid, and its stereo The group consisting of isomers and their combinations; a polar aprotic solvent; and a manual for the palm auxiliary agent; wherein, the polar aprotic solvent is at least one selected from ethyl acetate, tetrahydrofuran, A group consisting of acetonitrile, acetone and combinations thereof. The optical analysis kit according to claim 22, wherein the palm auxiliary agent is used in an amount of 0.5-2.0 eq. per molar equivalent of the stereoisomer mixture subjected to optical analysis. The optical analysis kit according to claim 22, wherein the manual for the palm assisting agent includes a description of the method defined in claim 1.