WO2017119666A1

WO2017119666A1 - Chiral resolution method for n-[4-(1-aminoethyl)-phenyl]-sulfonamide derivative using polar aprotic solvent

Info

Publication number: WO2017119666A1
Application number: PCT/KR2016/015402
Authority: WO
Inventors: 우병영; 이기화; 노종화; 박제홍; 박미영; 박영호
Original assignee: (주)아모레퍼시픽
Priority date: 2016-01-04
Filing date: 2016-12-28
Publication date: 2017-07-13
Also published as: KR102565407B1; KR20170081315A; TWI725098B; JP2019501923A; CN108473418A; JP6911033B2; TW201726585A

Abstract

The present invention relates to a chiral resolution method for a stereoisomeric mixture, the method comprising a step for mixing a stereoisomeric mixture of a compound, in which an amine group is attached to an asymmetric carbon atom, and a chiral auxiliary. Here, the chiral auxiliary is 2,3-dibenzoyl-tartaric acid or O,O'-di-p-toluoyl tartaric acid. An optical isomer having a high level of optical purity may be obtained by this method. Moreover, according to this method, the ratio of the stereoisomeric mixture contained in a mother liquid may be adjusted through recovery of the optical isomer. Therefore, in the pharmaceutical or medicinal field, a method according to an aspect of the present invention may be usefully used when attempting to obtain at high purity, a compound having a single type of optical isomer, and may be usefully used in the racemization of a mother liquid used in another reaction.

Description

Chiral splitting method of N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative with polar aprotic solvent

Disclosed herein is a chiral cleavage method of an N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative.

Recently, the demand for three-dimensional pure compounds is increasing rapidly. One important use for such pure stereoisomers is as an intermediate for synthesis in the pharmaceutical industry. For example, it is becoming increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. These advantages are described in, for example, Tinson, S.C., Chem Eng News, Sept. 28, 1992, pp. 46-79] often include fewer side effects and greater efficacy associated with enantiomerically pure compounds.

For example, triadimenol can have four isomers, the (-)-(1S, 2R) -isomer is the (+)-(1R, 2R) -isomer and the (-)-(1S, 2S). The) -isomers are more active than the (+)-(1R, 2S) -isomers, respectively. Dichlorobutrazole is known to have high activity of (1R, 2R) -isomer among four isomers. Also, it is known that the compound of etaconazole has a higher bactericidal effect than the other isomers of (+)-(2S, 4S)-and (-)-(2S, 4R) -isomers.

Therefore, if only one isomer having a high activity can be selectively prepared, a high effect can be obtained by using a small amount, and thus there is an advantage of reducing environmental pollution due to the use of chemicals. Especially in the case of pharmaceuticals, it is very important that only one isomer be prepared when one isomer is toxic to the human body.

Therefore, in the fields of medicine, pharmaceuticals, biochemistry, and the like, it is extremely important to prepare an optically pure compound for the purpose of improving drug efficacy per unit and preventing weakness due to side effects.

Vanilloid antagonists, including, for example, N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivatives, have been shown to have an effect on pure stereoisomers. [Examples: WO2008-013414 A1, WO2007-133637 A2 , WO2007-129188 A1, WO2010-010934 A1].

A synthesis method for preparing a homoisomer for such an N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative is known as an asymmetric synthesis method using an Elman adjuvant. For example, WO2008-013414 A1, WO2007-133637 A2, WO2007-129188 A1, and WO2010-010934 A1 provide a method for obtaining a desired stereoisomer by introducing an Elman adjuvant and inducing asymmetric reduction using the same. . However, this method must maintain a low temperature reaction to increase the optical purity (enantiomer excess,% ee) and is dangerous because it involves excessive hydrogen generation and exotherm at the end of reaction. There are limitations in terms of processing and economics.

[Preceding technical literature]

[Patent Documents]

WO2008-013414 A1

WO2007-133637 A2

WO2007-129188 A1

WO2010-010934 A1

Prior art related methods for the asymmetric synthesis of N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivatives have been reported, but preparations for commercial use have not yet been established due to economics and safety. Therefore, the present specification is to solve the problems of the conventional asymmetric synthesis method and to consider the economics and process safety, it is an object of the present invention to provide a novel method for chiral partitioning a stereoisomer mixture using a polar aprotic solvent. .

In order to achieve the above object, the present invention is, in one aspect, a chiral auxiliary having an optical activity of the N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative having a structure of Formula 1 Using N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative salt to provide a method of separating the respective compounds with high optical purity.

[Formula 1]

In more specifically, a polar aprotic solvent (R, S) - N - [4- (1- Amino-ethyl) -phenyl] - a mixture of a chiral auxiliary body having a sulfonamide derivative and the optically active (R) - Or (S) -type optically active N- [4- (1-aminoethyl) -phenyl] -sulfonamide diacyl tartrate salt or solvate thereof, and then prepared optically active N- [4- ( (R, S comprising the step of liberating 1-aminoethyl) -phenyl] -sulfonamide salt or solvate with base to produce optically active N- [4- (1-aminoethyl) -phenyl] -sulfonamide ) - N - [4- (1-aminoethyl) -phenyl] relates to a method for separating a sulfonamide - [4- (1-aminoethyl) phenyl] N having a high optical purity from a sulfonamide.

According to this method it is possible to chirally divide the N- [4- (1-aminoethyl) -phenyl] -sulfonamide derivative into the respective compounds with high optical purity.

N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide is a generic name of a compound represented by the following formula (2), TRPV1 (transient receptor potential cation channel subfamily V member 1, Or capsaicin receptor, vanilloid receptor 1) is known to be useful as an intermediate for preparing compounds that act as antagonists.

[Formula 2]

As represented by Formula 2, N- [4- (1-aminoethyl) -difluorophenyl] -methanesulfonamide is a chiral compound in which carbon bonded to an amine group is present as an asymmetric carbon.

According to the chiral splitting method according to an aspect of the present invention, a stereoisomer mixture, particularly a stereoisomer mixture of a compound having an amine group bonded to an asymmetric carbon atom, can be easily chiral split into a compound having high optical purity. This method is a synthetic method that improves safety and economics at the time of manufacture compared to the asymmetric synthesis method using the Elman assistant, and performs chiral splitting with an optical purity equal to or higher than that, and also shows high economical efficiency and eco-friendliness by collecting and reusing salts. Therefore, this method can be usefully used in the preparation of raw materials in the pharmaceutical and cosmetic fields that require chiral splitting of compounds.

In particular, the method according to an aspect of the present invention obtains the desired stereoisomer with an optical purity equal to or higher than that of the conventional asymmetric synthesis method using the Elman adjuvant and exhibits an efficient and economical effect in mass production.

In addition, according to the method according to an aspect of the present invention, it is possible to control or prepare the filtrate of the stereoisomer mixture with a racemate mixed with the S- and R-isomers in a ratio of about 1: 1, and separate racemization It shows the effect of racemization only through chiral cleavage of stereoisomer compounds with high purity without undergoing a reaction. Therefore, according to one aspect of the present invention, the filtrate can be used in another chiral splitting process without a separate process, and thus, it is possible to economically utilize the compound without losing a compound, unlike a general racemization reaction. Indicates.

In one aspect, the invention comprises mixing a stereoisomer mixture of a compound under a solvent with a chiral auxiliary to precipitate an enantiomeric excess of the diastereomeric salt of the compound and the chiral assistant. It may be directed to a chiral resolution method of stereoisomeric mixtures.

In one aspect of the invention, the chiral auxiliary body is a 2,3-dibenzoyl tartaric acid (2,3-dibenzoyl tartaric acid), O, O '- di - p - toluoyl-tartaric acid (O, O' -di- p -toluoyl tartaric acid), their stereoisomers, and combinations thereof.

As used herein, the term "in the enantiomeric excess" generally encompasses all increases in the proportion of enantiomers, and therefore the ratio of enantiomers as well as the enantiomeric ratio as compared to the racemic mixture is 1: 1 ( Compared to other mixtures (such as semibodies). In one aspect of the invention, the term "in mirror image excess" means that the mirror image excess (% ee) is at least 80%, at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, 92 It may correspond to at least%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. Similarly, the term "high optical purity" herein corresponds to a term well known in the art. In one aspect of the invention, the term "high optical purity" is at least 80%, at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at 95%. Or more, 96% or more, 97% or more, 98% or more, or 99% or more.

The chiral adjuvant herein can be obvious to those skilled in the art, and specifically, in the synthesis of organic compounds, temporarily to the synthesis process to control the stereochemical results of the synthesis. It can mean a compound to be incorporated, and such chiral auxiliaries may exist as an adjuvant to determine the steric selectivity of one or more series of reactions (see the chiral auxiliary page of Wikipedia (http://en.wikipedia.org/wiki). / Chiral_auxiliary)). Chiral assistants and chiral acids can be used interchangeably herein.

In one aspect of the invention, 2,3-dibenzoyl-tartaric acid is (+)-2,3-dibenzoyl-D-tartaric acid or (-)-2,3-dibenzoyl-L-tartaric acid which are optical isomers of each other one can, O, O '- di - p - toluoyl-tartaric acid are enantiomers of each other (+) - O, O' - di - p - toluoyl -D- tartaric acid or (-) - O, O ' - Di- p -toluoyl-L-tartaric acid. In the case of such tartaric acid derivatives, D-type and L-type can be used individually or mixed, but it is preferable to use them without mixing with each other. When used in the method according to one aspect of the present invention by combining the optical isomers D-type and L-type of the tartaric acid derivative, the optical purity value is lower than that of using D-type or L-type, respectively.

In one aspect of the invention, the stereoisomer mixture may be a stereoisomer mixture of a compound having an asymmetric carbon atom. Specifically, in one aspect of the present invention, the compound having an asymmetric carbon atom may be bonded to an amine group. Specifically, in one aspect of the present invention, the compound may be one having a substituted or unsubstituted phenyl group bonded to an asymmetric carbon atom in addition to the amine group. Further specifically, in one aspect of the present invention, the compound having an asymmetric carbon atom may be a compound having a structure of formula (1).

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

In one aspect of the invention, the method further chiral auxiliary body (+) - 2,3-dibenzoyl -D- tartaric acid, (+) - O, O '- di-p-toluoyl tartaric acid, and -D- In the case of one selected from the group consisting of a combination thereof, it may be a method of obtaining the S type optical isomer of the compound in a high enantiomeric excess.

In one aspect of the invention, the method further chiral auxiliary bodies (-) - 2,3-dibenzoyl -L- tartaric acid, (-) - O, O '- di-p-toluoyl tartaric acid, and -L- In the case of one selected from the group consisting of a combination thereof, it may be a method of obtaining the R-type optical isomer of the compound in a high enantiomeric excess.

In one aspect of the invention, the compound may have a structure of formula (1).

[Formula 1]

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are H; -NH ₂ ; An alkyl group of C _1-6 ; Alkenyl group of C _2-6 ; Alkynyl groups of C _2-6 ; And halogen is one selected from the group consisting of, R _One And R _{2 It} is to have a different substituent.

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

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

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

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

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

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

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

In one aspect of the invention, the solvent may be added in an amount to dissolve all the mixture. Specifically, in one aspect of the present invention, the solvent may be 2-80 times the total weight of the stereoisomer mixture, specifically 5-30 times, more specifically 5-15 times, more specifically 10 times the number (Ie, volume (solvent) / mass (stereoisomer, or (v / w)) In one aspect, the solvent is at least 2 times, at least 5 times, at least 10 times, at least 20 times the total weight of the stereoisomer mixture. More than 30 times, more than 40 times, more than 40 times, more than 50 times, more than 60 times, more than 70 times or more than 80 times or more than 80 times, less than 70 times, less than 70 times, less than 60 times, less than 50 times, less than 40 times, less than 40 times, 30 times 20 times or less, 15 times or less, 10 times or less, or 5 times or less.

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

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

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

In one aspect of the invention, the temperature is at least 30 ℃, at least 40 ℃, at least 50 ℃, at least 60 ℃, or at least 70 ℃, 70 ℃ or less, 60 ℃ or less, 50 ℃ or less, 40 ℃ or less, or 30 Or less. Specifically, the temperature may be 40 ° C. or more and 60 ° C. or less, more specifically 45 ° C. or more and 55 ° C. or less, and more specifically 50 ° C. or more.

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

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

In one aspect of the present invention, the equivalence ratio of the chiral auxiliary agent is 0.10 equivalents, 0.2 equivalents, 0.3 equivalents, 0.4 equivalents, 0.5 equivalents, 0.6 equivalents, 0.7 equivalents to 1 molar equivalent of stereoisomer mixture. At least 0.8 equivalents, at least 0.85 equivalents, at least 0.90 equivalents, at least 0.95 equivalents, at least 1.0 equivalents, at least 1.05 equivalents, at least 1.1 equivalents, at least 1.15 equivalents, at least 1.2 equivalents, at least 1.3 equivalents, at least 1.4 equivalents, at least 1.5 equivalents, Or 2.0 equivalents or less, 2.0 equivalents or less, 1.5 equivalents or less, 1.4 equivalents or less, 1.3 equivalents or less, 1.2 equivalents or less, 1.14 equivalents or less, 1.1 equivalents or less, 1.05 equivalents or less, 1.0 equivalents or less. It may be up to 0.95 equivalents, up to 0.90 equivalents, up to 0.85 equivalents, up to 0.8 equivalents, up to 0.7 equivalents, up to 0.6 equivalents, up to 0.5 equivalents, up to 0.4 equivalents, up to 0.3 equivalents, up to 0.2 equivalents, or up to 0.10 equivalents.

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

In one aspect of the present invention, the method comprises recovering the precipitated diastereomeric salts in the mother liquor after the step of enantiomeric precipitation of the diastereomeric salts of the compound having the structure of Formula 1 and the chiral assistant It may further comprise the step of adjusting the ratio of the R isomer: S isomer is 3: 7 to 7: 3 of the stereoisomer mixture. Specifically, in one aspect of the present invention, the step of adjusting the ratio of the R-type isomers to the S-type isomers may include the ratios of 3: 7 to 7: 3, 4: 6 to 6: 4, and 7: 8 to 8: 7. , 9:11 to 11; 9, 12:13 to 13:12, or the ratio of about 5: 5.

In one aspect, the present invention provides at least 80% ee, at least 82% ee, at least 84% ee, at least 86% ee, at least 88% ee obtained by dividing from the stereoisomeric mixture by the method according to one aspect of the invention. , At least 90% ee, at least 92% ee, at least 94% ee, at least 96% ee, at least 97% ee, at least 98% ee, or at least 99% ee.

In one aspect of the invention, the stereoisomer is N- {4-[(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide or N- {4-[(1S)- 1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide.

In one aspect of the present invention, an asymmetric carbon atom refers to carbon when a carbon atom in a molecule is bonded to four different atoms, atomic groups, or functional groups. Compounds containing such asymmetric carbon atoms have optical rotation, optical activity or optical isomers.

In one aspect of the invention, the stereoisomer mixture may mean that two enantiomers are mixed as an isomeric compound having optical activity, wherein the mixing ratio may be 1: 1 (in this case the racemic mixture is ), Or the mixing ratio may correspond to a ratio of integers between 1:10 and 10: 1. In one aspect of the invention, the stereoisomer mixture may be artificially synthesized or may be a mixture in a state in which the ratio of the R-type and S-type optical isomers is unknown. According to the method of the present invention, the ratio of the optical isomers of either the R type or the S type can be significantly increased, so that the optical isomer of the desired type can be obtained with high optical purity irrespective of the ratio of the mixture.

In one aspect of the invention, N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide is a compound of CAS No. 1202743-51-8 which corresponds to a molecular weight of 250.27 Da It can be used interchangeably with INT-2 within the present specification, which may be a stereoisomer mixture in which optical isomers of R or S type are mixed.

In one aspect of the invention, N- {4-[(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide hydrochloride corresponds to CAS No. 956901-23-8 The molecular weight corresponds to 286.73 Da, the component N- {4-[(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide corresponds to CAS number 957103-01-4 I mean. It can also be used interchangeably with the R-type isomer of INT-3 within this specification.

In one aspect of the invention, 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid corresponds to CAS No. 1005174-17-3, the molecular weight of 259.22 Da it means.

In one aspect of the invention, (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-trifluoro Romethyl-pyridin-3-yl) -acrylamide (PAC-14028) corresponds to CAS number 1005168-10-4 and means molecular weight 491.47 Da.

In one aspect of the invention, the R- or S-type optical isomers of INT-3 can be obtained according to the following method:

Mixing INT-2 (N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide) with a chiral assistant;

Adding 10 times (v / w) of polar aprotic solvent to INT-2 weight to the mixture;

Stirring the mixed solution to which the polar aprotic solvent is added at reflux at 30 ° C. to 70 ° C. for 1 to 4 hours;

Cooling the stirred mixture;

Filtering the solid produced by cooling to obtain an INT-3 chiral acid salt.

In one aspect of the invention, the cooling may be to cool to 15 ℃ ~ 30 ℃ after reflux.

In one aspect of the present invention, the cooling is at least 10 ° C, at least 15 ° C, at least 20 ° C, at least 22 ° C, at least 24 ° C, at least 25 ° C, at least 26 ° C, at least 28 ° C, at least 30 ° C, or at least 35 ° C. Or 40 ° C or less, 35 ° C or less, 30 ° C or less, 28 ° C or less, 26 ° C or less, 25 ° C or less, 24 ° C or less, 22 ° C or less, 20 ° C or less, 15 ° C or less, 10 ° C or less, or 5 ° C or less May be cooled to temperature.

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

In one aspect, the present invention may be directed to a chiral splitting method of stereoisomeric mixtures comprising the following steps:

(1) mixing a stereoisomer mixture of a compound having an amine group bonded to an asymmetric carbon atom with a chiral assistant.

In one aspect of the invention, the chiral auxiliary body in the above-mentioned (1) comprises 2,3-benzoyl- consisting of toluoyl tartaric acid, their stereoisomers, and their combinations - tartaric acid, O, O '- di-p It may be one or more selected from the group.

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

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

In one aspect of the invention, the method may further comprise the step of stirring the reflux (3) the mixed solution to which the solvent is added.

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

In one aspect of the invention, the stirring in step (3) is at least 20 ℃, at least 25 ℃, at least 30 ℃, at least 35 ℃, at least 40 ℃, at least 45 ℃, at least 50 ℃, at least 55 ℃, or 60 Stirred at a temperature above < RTI ID = 0.0 > C, < / RTI > It may be to stir at the following temperature.

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

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

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

In one aspect of the invention, the step (6) may include the step 1) injecting water and ammonia aqueous solution to the diastereoisomeric salt of INT-3. Specifically, in one aspect of the present invention, in step (6), the water is at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, or at least 7 times the weight ratio of the INT-3 diastereoisomeric salts. Or 7 times or less, 6 times or less, 5 times or less, 4 times or less, 3 times or less, or 2 times or less. Specifically, in one aspect of the present invention, the aqueous ammonia solution in step (6) is at least 20% by volume, at least 24% by volume, at least 28% by volume, at least 32% by volume, at least 36% by volume, or at least 40% by volume of ammonia Or 40% or less, 36% or less, 32% or less, 28% or less, 24% or less, or 20% or less by volume of an aqueous ammonia solution. Specifically, in one aspect of the present invention, the aqueous ammonia solution in step (6) is 0.5 equivalent or more, 1 equivalent or more, 1.5 equivalents or more, 2 equivalents or more, 2.5 equivalents or more, or 3 equivalents or more, or 4 equivalents or less, 3.5 equivalents Hereinafter, 3 equivalents, 2.5 equivalents, 2 equivalents, 1.5 equivalents, 1 equivalents, or 0.5 equivalents can be added.

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

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

In one aspect of the present invention, step (6) may further comprise the step 4) removing the filtered suspension with reduced pressure vacuum to obtain the R-type or S-type optical isomer of INT-3.

According to an aspect of the present invention, there is provided a method of chiral separation of a stereoisomer mixture of a compound having the structure of Chemical Formula 1 by a method according to an aspect of the present invention; And converting the divided stereoisomer into a compound having a structure of Formula 3a or 3b.

[Formula 3a]

[Formula 3b]

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are H; -NH ₂ ; An alkyl group of C _1-6 ; Alkenyl group of C _2-6 ; Alkynyl groups of C _2-6 ; And halogen is one selected from the group consisting of,

R ₁ and R ₂ may be related to a method for preparing a compound having a structure of Formula 3a or 3b having different substituents. The converting step is also described in detail in Korean Patent Application No. 10-2009-7004333.

In one aspect of the invention, the compound having a structure of formula 3a is (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide (PAC-14028), wherein the compound having the structure of Formula 1 is N- {4-[(1R / S) -1 -Aminoethyl] -2,6-difluorophenyl} methanesulfonamide.

In one aspect of the invention, the step of converting the divided stereoisomer into a compound having a structure of formula 3a or 3b is N- {4-[(1R) -1-aminoethyl] -2,6-difluoro And coupling 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (INT-7) with rophenyl} methanesulfonamide (INT-3). .

The stereoisomers divided by the method according to one aspect of the present invention can be used as intermediates in the preparation of new drugs described in the application by reacting with the substances described in Korean Patent Application No. 10-2009-700433. Therefore, in one aspect, the present invention is a method for preparing a novel drug described in Korea Patent Application No. 10-2009-700433 or prepared by such a method using stereoisomers divided by the method according to an aspect of the present invention. To a new drug.

In one aspect, the present invention provides a (R) -N- [1- () having at least 96%, at least 97%, at least 98%, or at least 99% of the enantiomeric excess produced by the method according to one aspect of the present invention. 3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide.

In one aspect, the present invention provides (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl]-produced by the method according to one aspect of the present invention. It may be related to a TRPV1 antagonist comprising 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide (PAC-14028) as an active ingredient. Such TRPV1 antagonists can be used as pharmaceutical compositions for the prevention or treatment of the diseases described below.

The invention in one aspect, (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2 according to one aspect of the invention Pain, inflammatory diseases of the joints, including -propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide, its optical isomer, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, Neuropathy, HIV-related neuropathy, nerve damage, neurodegeneration, stroke, urinary incontinence, cystitis, gastric-duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), stool deficiency disease, gastroesophageal reflux disease ( GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurological / allergic / inflammatory skin disease, psoriasis, pruritus, positive, skin irritation, inflammation of the eye or mucous membranes, auditory hypersensitivity, tinnitus, vestibular hypersensitivity, episodes Myocardial ischemia, hair loss, alopecia, alopecia, rhinitis and pancreatitis Carbonyl can relate to a pharmaceutical composition for the prevention or treatment of diseases which are associated with the pathological stimulation and / or over expression of the receptor Lloyd.

In one aspect of the invention, the pain is in the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, toothache, fibrositis, myofascial pain syndrome, back pain, migraine and other types of headache It may be the disease selected or pain associated with the disease.

The present invention in one aspect, chiral auxiliary; Polar aprotic solvents; It may be related to the optical splitting kit comprising; and instructions for using the chiral assistant.

In one aspect of the invention, the chiral auxiliary may be at least one selected from the group consisting of 2,3-dibenzoyl tartaric acid, O, O'-di- p -toluoyl-tartaric acid, their stereoisomers, and combinations thereof. have.

In one aspect of the invention, the chiral auxiliary may be from 0.5 to 2.0 equivalents per mole equivalent of the stereoisomer mixture to be optically split.

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

In one aspect of the present invention, the instructions for use in the use of the optical splitting agent, 0.5 to 2.0 equivalents, specifically 0.8 to 1.5 equivalents of chiral auxiliary per 1 molar equivalent of the stereoisomer mixture to be optically divided It may include that the content.

In one aspect of the invention, the instructions for use may include the content of mixing with the stereoisomer mixture under polar aprotic solvents when using chiral auxiliaries.

In one aspect of the invention, the instructions may be a description of the chiral separation method of the stereoisomer mixture according to an aspect of the present invention.

Hereinafter, the present invention will be described through the following examples and test examples. Examples and test examples are intended to explain the present invention in more detail, but the scope of the present invention is not limited to the scope of the following examples. In addition, it is obvious that any person skilled in the art can make various modifications and imitations within the scope of the appended claims without departing from the scope of the technical idea of the present invention.

Comparative Test Example 1 Measurement of Optical Purity by Conventional Asymmetric Synthesis

The conventional asymmetric synthesis was carried out as in Scheme 1 below.

Scheme 1

N- {2,6-difluoro-4- [1- (2-methyl-propane-2-sulfinylimino) -ethyl] -phenyl} -methanesulfonamide (1 equiv) of its weight It was added to and dissolved in tetrahydrofuran (THF) (20 mL) corresponding to 10-fold, and further dissolved NaBH ₄ (4 equivalents) in the solution, followed by reaction for 10 hours at the temperature shown in Table 1 below. Proceeded. CH ₃ OH was then added dropwise until no more hydrogen gas was released.

The mixture was concentrated under reduced pressure and then purified by chromatography to give N- {2,6-difluoro-4- [1- (2-methyl-propane-2-sulfinylamino) -ethyl] -phenyl} -Methanesulfonamide was obtained. 4 M HCl in dioxane was added dropwise and the mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The crude residue was purified by recrystallization with acetone to give (R) -N- [4- (1-amino-ethyl) -2,6-difluoro-phenyl] -methanesulfonamide, HCl salt.

The salt thus obtained was subjected to the same process as in the test example below to determine the mirror image excess, and is shown in Table 1 below.

According to the conventional method, in order to obtain an optical activity of 96% or more, as shown in Table 1, the temperature of -40 ° C. or less must be maintained for 10 hours, but according to the present invention, the same optical activity is stirred and solvent at a temperature of 50 ° C. It can be achieved only by the step of refining. Thus, it can be determined that the method of the present invention is significantly economical as compared to the conventional method. In addition, in the case of scaling up the reaction on a factory basis, it is much easier to maintain a temperature of 50 ° C. than to maintain a temperature of −40 ° C. for 10 hours. Compared to this, the scale of the reaction can be more easily scaled up.

In addition, since the conventional method uses 2 to 4 equivalents of sodium borohydride, an excessive amount of explosive hydrogen is generated and heat is generated during the final termination of the reaction, which is a process involving a very dangerous reaction. . However, on the contrary, the present invention has a feature of exhibiting a heterogeneous effect of obtaining stereoisomers having commercially available optical activity without involving dangerous processes such as excessive generation of explosive hydrogen or generation of heat. .

Therefore, according to these results, the present invention corresponds to a method involving a process that is more economical and safe than the conventional method.

[Comparative Test Example 2] Measurement of the Form of Separation and Optical Purity in the case of Separation Using Polar Quantum Solvent

N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide according to the preparation method described in Bioorganic & Medicinal Chemistry (15 (18), 6043-6053; 2007) As a mixture of R and S isomers, R: S = 1: 1) was prepared. The N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide thus prepared and the optical dividing agent (purchased from Sigma Aldrich) shown in Table 2 were each mixed in an equivalent amount. . This mixed mixture was subjected to 10 times the number of solvents with respect to the weight of N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide (different polar proton solvents according to Table 1 below). ) Was added. The solvent-added mixed solution was refluxed at 50 ° C. for 3 hours and then cooled to 25 ° C. The resulting solid was filtered with Buchner funnel to give the respective N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide chiralate.

To each N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide chiral acid salt thus obtained was added 5 equivalents of weight ratio water and 2 equivalents of an aqueous 28% by volume ammonia solution. The suspension obtained by stirring for 30 minutes was filtered through a Buchner funnel and the excess water was removed by vacuum to remove N- [4-[( 1R ) -1-aminoethyl] -2,6-difluoro. Phenyl] -methanesulfonamide or N- [4-[( 1S ) -1-aminoethyl] -2,6-difluorophenyl] -methanesulfonamide.

Optical purity (over mirror phase excess) of the INT-3 thus obtained was analyzed by a chiral HPLC column (Shiseido Chiral CD-Ph 4.6 mm × 250 mm, 5 μm). 0.5 mol / L sodium perchlorate and methanol mixture (75% by volume: 25% by volume) were used as the mobile phase, and the ratio of each chiral acid salt separated into a solid under the following conditions was measured using Waters e2695 Alliance HPLC. Equation 1 can be used based on the ratio of each salt to calculate the optical purity (en%) of each salt.

The measurement results for the ratio of each salt are shown in Table 1 below.

1. Column Temperature = 35 ℃

2. flow rate = 0.5 ml / min,

3. Detection = 220 nm

4.Rt (min) = 20.4 (% of R-enantiomer), 18.9 (% of S-enantiomer)

[Equation 1]

* When L-type chiral auxiliaries are used, the ratio of the R-type and S-type isomers is obtained in reverse.

According to these results, it can be seen that when using a polar protic solvent, unlike the method according to the present invention, R type isomers can be separated and obtained using a D type chiral auxiliary. In addition, when using a solvent in which the isopropyl alcohol, which is a polar protic solvent, and the acetone, which is a polar aprotic solvent, were mixed in a 1: 1 ratio, the R-type and S-type isomers were obtained in the same ratio. When a mixture of solvents having different properties was used, it was confirmed that the separation of the stereoisomer mixture was not performed.

[Test Example 1] Confirmation of Separation When Separation Using Polar Aprotic Solvent

According to the method described in Comparative Test Example 2 above, the experiment was performed using the polar aprotic solvent described in Table 3, but not the polar protic solvent. In this case, the ratio of each isomer separated as a solid was measured under HPLC conditions of Comparative Test Example 2, and the results are shown in Table 3.

According to the above results, when the D-type chiral auxiliary is reacted with the stereoisomer mixture in a polar aprotic solvent by the method according to an aspect of the present invention, the S-type stereoisomer is obtained at a higher ratio in most polar aprotic solvents. It could be confirmed. In the case of dimethylformamide and dimethyl sulfoxide, N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide chiralate is present in all dissolved solvents and separated as a solid It could not be determined whether it was separated.

For the acetone in which the S-type isomer was obtained at the highest ratio among these polar aprotic solvents, the equivalent weight of the chiral auxiliary was adjusted as follows and the ratio of the R-isomer and S-isomer in the stereoisomer mixture was adjusted. The ratio and yield of the isomer compound to be measured were measured.

Test Example 2 Measurement of Ratio and Yield According to Equivalence of Chiral Auxiliaries Using Acetone Solvent

The experiment was carried out according to the method described in Comparative Test Example 2, but acetone was used as a solvent, and the equivalent of the chiral auxiliary was carried out differently as described in Table 4 below. The ratio of each isomer separated as a solid was measured by HPLC conditions of Comparative Test Example 2, and the reaction yield was calculated by the following Equation 2. These results are shown in Table 4.

[Equation 2]

Actual yield: amount of product actually obtained

Theoretical yield: the maximum mass of product obtainable from a given mass of reactant

According to the results, it was confirmed that the ratio and yield of isomers obtained as a solid vary depending on the equivalent of the stereoisomer mixture and the chiral auxiliary. Separation of the S-type isomer was carried out when the equivalent of the chiral auxiliary to 1 equivalent of the stereoisomer mixture was 1 equivalent or more, and the ratio of the S-isomer was the highest when the equivalent of the chiral auxiliary was 1.2 equivalents, and S The highest yield in the case of separation of the isomers was 1.2 equivalents of the chiral auxiliary.

Test Example 3 Measurement of Optical Purity and Yield According to the R: S Ratio of the Stereoisomeric Mixture and the Equivalent of the Chiral Auxiliaries

The experiment was carried out according to the method described in Comparative Experimental Example 2, wherein the ratio of R and S type isomers in N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide was 14: The experiment was carried out at 86, and the experiment was performed by varying the equivalents of the chiral assistants as shown in Table 5. The ratio of each isomer separated as a solid was measured by HPLC conditions of Comparative Test Example 2, and the reaction yield was calculated by the above Equation 2.

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

* In the case of using L-type chiral auxiliaries in Tables 5 to 7, the ratio of R-type isomers and S-type isomers is obtained in reverse.

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

With respect to 1 equivalent of stereoisomer mixture, the S-type isomer compound was obtained in higher proportion compared to the stereoisomer mixture before the reaction when the chiral auxiliary was 1 equivalent or more. In particular, when the chiral auxiliaries were 1.0 equivalent, the ratio of the S-form isomer separated as a solid was 97% and the yield was 74%.

In particular, when the chiral auxiliary was 1.0 equivalent, the ratio of R isomers to S isomers was controlled to 45:55 in the isomer mixture remaining in the reaction mother liquor after obtaining the S type isomer compound which precipitated as a solid. It shows that only S-types are selectively separated.

In addition, in the case of Table 6 in which the ratio of the R-isomer to the S-isomer is 25:75 and Table 7 in which the ratio of the S-isomer is 25:75 and 10:90 in the stereoisomer mixture, the S-type isomeric compound was obtained at a higher ratio compared to the results of Table 4. Could be obtained.

Specifically, the S-type isomer compound was obtained at a higher ratio compared to the stereoisomer mixture before the reaction when the chiral auxiliary was 1 equivalent or more with respect to 1 equivalent of the stereoisomer mixture. In particular, when the chiral auxiliary was 1.0 equivalent, the highest ratio of the S-form isomers separated into solids was 88% and 98%, respectively, and the yields were 72% and 76%, respectively. As can be seen from the results in Table 6, when the R: S ratio is 25:75, and the chiral auxiliary is 1.2 equivalents, the ratio of R: S remaining in the filtrate after separation of the isomeric compound as a solid is 51:49. You can see that it is adjusted to.

Therefore, according to one aspect of the present invention, it is possible to selectively separate only the S-type isomer compound from the stereoisomer mixture having a higher proportion of S-type at a higher ratio, and after performing this separation method, R contained in the mother liquor Since the ratio of the isomer and the S isomer is almost 1: 1, the stereoisomer mixture can be separated into the racemate by removing only the S isomer.

In addition, the separated high optical purity S-type isomeric compounds may be able to obtain racemates of stereoisomer compounds through other racemization processes.

Therefore, the method according to one aspect of the present invention has the advantage that the racemization can be carried out using a stereoisomer mixture while minimizing the loss of R-type isomers, and that the racemates thus obtained can be used again for other reactions. Have

In addition, the method according to one aspect of the present invention can minimize the loss of the R-type isomer by the racemization process and can be racemized from the S-type by only racemization of the isolated S-type selectively. Thus, according to one aspect of the present invention, the S-type isomer can be separated from the stereoisomer mixture in a high yield under a polar aprotic solvent and prepared similarly to the racemate so that the filtrate can be used again for the chiral splitting method. It is possible to do

In addition, according to the method according to an aspect of the present invention, after obtaining an R-isomer compound using a polar protic solvent and a D-type chiral auxiliary, a solid compound obtained by crystallizing the remaining filtrate with an aqueous ammonia solution (R: S 14:86) using the same D-type chiral auxiliaries and simply by converting them into polar aprotic solvents to selectively separate S-type isomeric compounds and use the mother liquor again for chiral splitting reactions. It can be prepared in a similar ratio (R: S is close to 1: 1), and it is also possible to prepare a racemic compound (R: S = 1: 1) by racemization of the separated S form. This is a method that minimizes the desired R-type loss and enables the preparation of racemic compounds. Therefore, the method according to one aspect of the present invention uses the same kind of chiral auxiliaries as the process for separating the R-isomers, so there is no cross-contamination by opposing chiral auxiliaries, which is advantageous for the process application. . Therefore, the R type isomer is obtained by changing only the solvent so that the filtrate containing the stereoisomer mixture which has undergone the chiral splitting method can be continuously recycled, and can be simply racemized and put back into the chiral splitting method. It is very economical and eco-friendly.

When using the L-type chiral auxiliaries in the method and the experiment according to one aspect of the present invention it will be possible to obtain the R-type stereoisomer compound, the R-type isomer compound is equivalent to INT-3 Likewise, it can be used in additional processes.

[Test Example 4] (R) -N- [1- (3,5-Difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl- Preparation of Pyridin-3-yl) -acrylamide

(R) -N- [1- using N- {4-[(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide prepared according to one aspect of the present invention. (3,5-Difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide in Korean Patent Application 10 It prepared according to the method described in -2009-7004333.

Specifically, N- {4-[(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide, HCl salt (62 mg, 0.22 mmol) was added to 3- (2-propyl-6. Reaction with -trifluoromethyl-pyridin-3-yl) -acrylic acid (56 mg, 0.22 mmol) crystallized with ether to give the title compound (81 mg, 73%).

¹ H NMR (300 MHz, 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 = 7.8 Hz), 7.67 (d, 1H, J = 15.6 Hz), 7.18 (d, 2H, J = 7.2 Hz), 6.76 (d, 1H, J = 15.6 Hz), 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-type isomer of the compound having the structure of Formula 1 divided according to one aspect of the present invention prepares various novel compounds that can act as TRPV1 antagonists by the materials or methods described in Korean Patent Application No. 10-2009-7004333. It can be usefully used as an intermediate required to do so.

Claims

As a chiral resolution method of stereoisomeric mixtures,

A stereoisomer mixture of a compound having the structure of Formula 1 is mixed with a chiral auxiliary in a polar aprotic solvent to enantiophorically exceed the diastereomeric salt of the compound having the structure of Formula 1 with the chiral assistant Precipitating in a quantity;

[Formula 1]

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are H; -NH 2 ; An alkyl group of C 1-6 ; Alkenyl group of C 2-6 ; Alkynyl groups of C 2-6 ; And halogen selected from the group consisting of

Wherein R 1 and R 2 have different substituents, chiral resolution method of the stereoisomer mixture.
The method of claim 1,

Method at least one selected from tartaric acid, their stereoisomers, and the group consisting of a combination thereof, wherein the R 2 is hydrogen and the chiral auxiliary body is a 2,3-dibenzoyl-tartaric acid, O, O '- di-p-toluoyl.
The method of claim 1,

The method chiral auxiliary body (+) - 2,3-dibenzoyl -D- tartaric acid, (+) - O, O '- di-toluoyl -D- tartaric acid and one selected from the group consisting of a combination of - p Wherein, the S-type optical isomer of the compound of formula 1 is obtained in enantiomeric excess.
The method of claim 1,

The method car body chiral auxiliary (-) - 2,3-dibenzoyl -L- tartaric acid, (-) - O, O '- di-toluoyl -L- is selected from the group consisting of tartaric acid and a combination thereof - p Wherein, the R-type optical isomer of the compound of formula 1 is obtained in enantiomeric excess.
The method of claim 1,

Said halogen is at least one selected from the group consisting of F, Cl, Br and I.
The method of claim 5,

R 1 is one selected from the group consisting of methyl group, ethyl group, propyl group, butyl group, and pentyl group,

R 2 is hydrogen.
The method of claim 6,

R 1 is a methyl group,

R 3 and R 7 are hydrogen,

R 4 , R 5 , and R 6 are one selected from the group consisting of alkyl groups of F, Cl, Br, I and C 1-6 .
The method of claim 7, wherein

R 4 and R 6 are F,

R 5 is a methyl group,

Wherein the compound is N- {4-[(1R / S) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide.
The method of claim 1,

Wherein said polar aprotic solvent is at least one selected from the group consisting of ethyl acetate, tetrahydrofuran, acetonitrile, acetone and combinations thereof.
The method of claim 9,

Wherein said polar aprotic solvent is acetone.
The method of claim 1,

The polar aprotic solvent is added in an amount to dissolve all the mixtures.
The method of claim 11,

Wherein said polar aprotic solvent is 5-15 times (v / w) relative to the total weight of the stereoisomer mixture.
The method of claim 1,

Mixing in the process is carried out by increasing the temperature of the mixture to 40 ℃ to 70 ℃, the boiling point of the solvent or the boiling point of the solvent mixture.
The method according to any one of claims 1 to 13,

The equivalence ratio of the chiral assistant to 1 molar equivalent of the stereoisomer mixture is 0.5 to 2.0 equivalents.
The method of claim 14,

The equivalence ratio of the chiral assistant to 1 molar equivalent of the stereoisomer mixture is 0.8 to 1.5 equivalents.
The method of claim 14,

Wherein said stereoisomer mixture has a ratio of R-type isomers to S-type isomers from 1: 9 to 9: 1.
The method of claim 16,

Wherein said stereoisomer mixture has a ratio of R-type isomers to S-type isomers from 1: 3 to 1: 9.
The method of claim 14,

The method comprises recovering the precipitated diastereomeric salts and recovering the precipitated diastereomeric salts of the stereoisomer mixture of the compound having the structure of formula (I) and the chiral assistant in the enantiomeric mixture of the stereoisomer mixture contained in the mother liquor. : Further comprising adjusting the S-form isomer ratio from 3: 7 to 7: 3.
The method of claim 18,

The step of adjusting the ratio of the R-type isomer: S-type isomer is to adjust the ratio of 4: 6 to 6: 4.
At least 80%, at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, 96% obtained from the stereoisomer mixture by the method according to claim 14 At least 97%, at least 98%, or at least 99% of the stereoisomer of the compound of formula (I).
The method of claim 20,

The stereoisomer is N- {4-[(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide or N- {4-[(1S) -1-aminoethyl] -2 , 6-difluorophenyl} methanesulfonamide.
As a method for preparing a compound having a structure of Formula 3a or 3b,

The method comprises the steps of chiral partitioning a stereoisomer mixture of a compound having the structure of Formula 1 by the method of any one of claims 1 to 13; And

Converting the divided stereoisomer into a compound having a structure of Formula 3a or 3b,

[Formula 3a]

[Formula 3b]

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are H; -NH 2 ; An alkyl group of C 1-6 ; Alkenyl group of C 2-6 ; Alkynyl groups of C 2-6 ; And halogen selected from the group consisting of

R 1 and R 2 is a method for producing a compound having a structure of formula 3a or 3b having different substituents.
The method of claim 22,

Compound having the structure of Formula 3a is (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-tri Fluoromethyl-pyridin-3-yl) -acrylamide,

The compound having the structure of Formula 1 is N- {4-[(1R / S) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide.
The method of claim 22,

The step of converting the divided stereoisomer into a compound having a structure of Formula 3a or 3b is N- {4-[(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide (INT -3) and coupling 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (INT-7).
(R) -N- [1- (3,5-difluoro-4- with an enantiomeric excess of at least 96%, at least 97%, at least 98%, or at least 99% prepared by the method according to claim 22 Methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide.
2,3-dibenzoyl-tartaric acid, O, O '- di-p-toluoyl-tartaric acid, their stereoisomers, and one or more chiral auxiliary material selected from the group consisting of a combination thereof; Polar aprotic solvents; And instructions for use of the chiral adjuvant.
The method of claim 30,

The chiral assistant is 0.5 to 2.0 equivalents to 1 molar equivalent of the stereoisomer mixture to be optically divided.
The method of claim 30,

Instructions for use of said chiral adjuvant wherein the method of claim 18 is described.