KR20160101554A

KR20160101554A - Method for chiral resolution of derivatives of n-[4-(1-aminoethyl)-phenyl]-methanesulfonamide

Info

Publication number: KR20160101554A
Application number: KR1020150024334A
Authority: KR
Inventors: 우병영; 이기화; 신광현; 박미영; 정경미; 최준호; 최계영; 조원경; 박영호
Original assignee: (주)아모레퍼시픽
Priority date: 2015-02-17
Filing date: 2015-02-17
Publication date: 2016-08-25

Abstract

The present invention relates to a chiral resolving method for a stereomer mixture comprising a step of mixing the stereomer mixture of a compound, which is made by an amine group coupled with an asymmetric carbon atom, with a chiral auxiliary reagent and a salt-forming auxiliary compound. In the meantime, the chiral auxiliary reagent is a 2,3-dibenzoyl-tartaric acid or an O, O-di-p-toluoyl tartaric acid. The salt forming auxiliary compound is a mandelic acid or a camphoric sulfonic acid. According to the present invention, an optical isomer having a high degree of optical purity can be obtained. Therefore, the method according to an aspect of the present invention can be usefully utilized in a pharmacy or a pharmaceutical field when a compound having a single type of optical isomers is to be obtained at high purity.

Description

METHOD FOR CHIRAL RESOLUTION OF DERIVATIVES OF N- [4- (1-AMINOETHYL) -PHENYL] -METHANESULFONAMIDE} The present invention relates to a method for separating chiral N- [4- (1-aminoethyl)

The present invention relates to a chiral resolution method of N - [4- (1-aminoethyl) -phenyl] -methanesulfonamide derivative.

Recently, the demand for sterically pure compounds is rapidly increasing. One important use for such pure stereoisomers is their use as intermediates 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 (e.g., Stinson, 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 may have four isomers, the (-) - (1S, 2R) -isomer is the (+) - (1R, 2R) ) -Isomer is more active than the (+) - (1R, 2S) -isomer. Dichlorobutrazole is known to have a high activity of the (1R, 2R) -isomer among the four isomers. Also, it is known that the compound of Etaconazole has higher sterilizing effect than the other isomers of (+) - (2S, 4S) - and (-) - (2S, 4R) -isomers.

Therefore, if only one active isomer can be selectively produced, a high effect can be obtained by using a small amount, and thus there is an advantage that environmental pollution due to the use of a chemical can be reduced. Especially in the case of medicines, it is very important to produce only one isomer selectively when one isomer is toxic to the human body.

Therefore, in fields such as pharmaceuticals, pharmaceuticals, and biochemistry related industries, it is an extremely important problem to prepare an optically pure compound for the purpose of improving drug efficacy per unit and preventing the harmful effects caused by side effects.

For example, vanilloid antagonists comprising N - [4- (1-aminoethyl) -phenyl] -methanesulfonamide derivatives have been shown to be efficacious for pure stereoisomers [e.g., WO2008-013414A1, WO2007-133637 A2, WO 2007-129188 A1, WO2010-010934 A1].

A synthesis method for preparing a single isomer for such N - [4- (1-aminoethyl) -phenyl] -methanesulfonamide derivative is known as an asymmetric synthesis method using ELNA auxiliary. For example, WO2008-013414A1, WO2007-133637A2, WO2007-129188A1, and WO2010-010934A1 disclose a method for introducing an elvan auxiliary and inducing asymmetric reduction using the same to obtain a desired stereoisomer . However, this method requires a low temperature reaction in order to increase the optical purity (enantiomer excess,% ee), and it is dangerous because it involves excessive hydrogen generation and exothermic reaction during the reaction termination, and excessive organic and inorganic waste is generated after the reaction termination There are limitations in terms of processing and economics.

WO2008-013414 A1 WO 2007-133637 A2 WO 2007-129188 A1 WO2010-010934 A1

Although the prior art relating to the asymmetric synthesis of N - [4- (1-aminoethyl) -phenyl] -methanesulfonamide derivatives has been reported, the process for commercial utilization has not yet been established due to economics and safety. Accordingly, the present invention provides a novel method of solving the problems of the above conventional asymmetric synthesis method and considering the economical and safety of the process as a chiral segmentation of a stereoisomer mixture into an S or R type compound having a single optical activity .

In order to achieve the above object, the present invention provides, in one aspect, a process for preparing N - [4- (1-aminoethyl) -phenyl] -methanesulfonamide derivative by reacting an optically active chiral auxiliary with a salt- Is used to separate N - [4- (1-aminoethyl) -phenyl] -methanesulfonamide derivative salt into an optically active compound. More particularly, the present invention relates to a process for the preparation of (R, S) -N- [4- (1-aminoethyl) -phenyl] -methanesulfonamide derivative and a salt-forming auxiliary compound in a polar protic solvent, To prepare an optically active N - [4- (1-aminoethyl) -phenyl] -methanesulfonamide diacyl tartrate salt of the (R) - or (S) - type or a solvate thereof, The resulting optically active N - [4- (1-aminoethyl) -phenyl] -methanesulfonamide salt or solvate was isolated as an optically active N - [4- (1-aminoethyl) comprising the step of producing the (R, S) -N- [4- (1-aminoethyl) phenyl] - N, with a single optically active from methanesulfonamide [4- (1-aminoethyl) - Phenyl] -methanesulfonamide. &Lt; / RTI >

According to this method, it is possible to chirally divide N - [4- (1-aminoethyl) -phenyl] -methanesulfonamide derivative into a compound having only one optical activity easily.

N - [4- (1-aminoethyl) -phenyl] -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 ) &Lt; / RTI > antagonists.

(2)

As shown in Formula 2, N - [4- (1-aminoethyl) -phenyl] -methanesulfonamide is a chiral compound in which carbon bonded to an amine group exists as an asymmetric carbon (chiral center).

According to one aspect of the present invention, a stereoisomeric mixture, particularly a stereoisomer mixture of a compound having an amine group bonded to an asymmetric carbon atom, can be chirally divided into a compound having only one optical activity. This method is a synthetic method that enhances safety and economical efficiency in manufacturing compared with the asymmetric synthesis method using the elmann assistant, and performs chiral decomposition with an optical purity equal to or higher than that of the synthetic method. Further, the method exhibits high economical efficiency and environment friendliness by collecting and reusing salts. Therefore, this method can be usefully used in the production of raw materials for the field of pharmacy and cosmetics, in which chiral cleavage of the compound is required.

In particular, the method according to one aspect of the present invention produces a desired stereoisomer with an optical purity equal to or higher than that of the conventional asymmetric synthesis method using an E-assistant, and exhibits an efficient and economical effect in mass production.

In one aspect, the present invention relates to a process for the preparation of a compound of formula (I), wherein the stereoisomeric mixture of compounds is mixed with a compound of formula (I) with a chiral auxiliary and (ii) with an auxiliary salt- To a chiral resolution method of a stereoisomeric mixture comprising precipitating a diastereomeric salt of the chiral auxiliary with an enantiomeric excess.

In one aspect of the invention, the salt-forming auxiliary compound may be one or more selected from the group consisting of mandelic acid, camphorsulfonic acid, their stereoisomers, and combinations thereof. The effect of the present invention can not be achieved when acetic acid, benzoic acid, D / L-tartaric acid or quinic acid, which is capable of forming a soluble salt in addition to mandelic acid or camphorsulfonic acid, is used.

In one aspect of the invention, the chiral auxiliary is 2,3-dibenzoyl tartaric acid, O, O'-di- p -toluoyltartaric acid ( O, p- toluoyl tartaric acid, their stereoisomers, and combinations thereof. In addition, the chiral auxiliary herein can be used interchangeably with the chiral acid.

As used herein, the chiral auxiliary is a compound which can be easily recognized by a person skilled in the art to which the technical field of the present invention belongs. Specifically, in order to control the stereochemical result of synthesis in the synthesis of an organic compound, May refer to compounds that are incorporated, and such chiral auxiliaries may exist as adjuvants to determine the steric selectivity of one or more series of reactions (see Wikipedia chiral auxiliary page (http://en.wikipedia.org/wiki/Wiki/). / Chiral_auxiliary)).

As used herein, salt-forming auxiliary compounds are intended to assist the compound to be chiral cleaved and the chiral auxiliary to form an insoluble salt, wherein the isomer that does not form an insoluble salt with the chiral auxiliary among the stereoisomers of the compound To prevent precipitation so as to assist in obtaining an insoluble salt with a high enantiomeric excess.

In one aspect of the present invention, the 2,3-dibenzoyl-tartaric acid is (+) - 2,3-dibenzoyl-D-tartaric acid or (-) - 2,3-dibenzoyl-L-tartaric acid O, O'-di- p -toluoyltartaric acid is an optically isomeric (+) - O, O'-di- p -toluoyl-D-tartaric acid or (-) - O, Di- p -toluoyl-L-tartaric acid. In the case of such a tartaric acid derivative, D-type and L-type may be used individually or in combination, but it is preferable to use them without mixing with each other. When the optical isomer D of the tartaric acid derivative and the L-type are used in the method according to one aspect of the present invention, the optical purity value becomes lower than that of the D-type or L-type, respectively.

In one aspect of the invention, mandelic acid may be D-mandelic acid, L-mandelic acid, or a combination thereof, which are optical isomers with respect to each other, and camphorsulfonic acid is an optically isomeric (1R) - (- Sulfonic acid, (1S) - (+) - 10-camphorsulfonic acid, or a combination thereof. According to the following experimental examples, the optical isomer form of mandelic acid or camphorsulfonic acid has a small effect on the optical isomer form of the final product, and even with the use of different mandelic acid or camphorsulfonic acid optical isomers or combinations thereof, It is possible to obtain the final product in purity.

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

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

In one aspect of the present invention, the process is characterized in that the chiral auxiliary is selected from the group consisting of (+) - 2,3-dibenzoyl-D-tartaric acid, (+) - O, O'-di- p -toluoyl- When the compound is one selected from the group consisting of combinations thereof, the R-type optical isomer of the compound may be obtained in an enantiomeric excess.

In one aspect of the present invention, the process is characterized in that the chiral auxiliary is selected from the group consisting of (-) - 2,3-dibenzoyl-L-tartaric acid, (-) - O, O'-di- p -toluoyl- When the compound is selected from the group consisting of combinations thereof, the S-type optical isomer of the compound may be obtained in an enantiomeric excess.

In one aspect of the invention, the salt-forming auxiliary compound is selected from the group consisting of D-mandelic acid, L-mandelic acid, (1R) - (-) - 10- camphorsulfonic acid, (1S) - &Lt; / RTI > or a combination thereof.

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

[Chemical Formula 1]

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are independently selected from the group consisting of H; -NH ₂ ; A C _1-6 alkyl group; A C _2-6 alkenyl group; A C _2-6 alkynyl group; And halogen, and R < ₁ > and R < ₂ > have different substituents.

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

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

In one aspect of the invention, R ₁ is a methyl group, R ₃ and R ₇ are hydrogen, and R ₄ , R ₅ , and R ₆ are _{independently selected from} the group consisting of F, Cl, Br, I, Lt; / RTI >

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

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

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

In one aspect of the present invention, the polar protic solvent may be at least one selected from the group consisting of water, C _1-14 alcohol, isopropyl alcohol, acetic acid, nitromethane, propionic acid, formic acid, and combinations thereof. Specifically, the polar protic solvent may be at least one selected from the group consisting of water, methanol, ethanol, and isopropyl alcohol. More specifically, the polar protic solvent may be methanol or isopropyl alcohol, and more particularly the polar protic solvent may be isopropyl alcohol.

In one aspect of the invention, the solvent may be added in an amount to dissolve all of the mixtures. Specifically, in one aspect of the present invention, the solvent may be in the range of 5-15 times the total weight of the stereoisomeric mixture, specifically in the range of 7-13, more specifically 9-11, more specifically 10 have.

In one aspect of the present invention, the method may further comprise the step of (iii) increasing the temperature of the mixture to a boiling point of the solvent at 40 ° C to 70 ° C.

In one aspect of the present invention, the step (iii) may be a step of increasing the temperature while stirring for 1 to 4 hours.

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

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

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

In one aspect of the present invention, the method may be to react R-form or S-form two molecules of a compound having the structure of formula (1) per molecule of chiral auxiliary. In one aspect of the present invention, this reaction may be carried out as shown in Reaction Scheme 1 below.

[Reaction Scheme 1]

According to Reaction Scheme 1, two molecules of the compound of Chemical Formula 2 are bonded to one molecule of the chiral auxiliary, and the compound to be bonded at this time corresponds to one having an optical activity, and this bond forms an insoluble salt, . On the other hand, compounds that do not bind chiral auxiliaries dissolve in salt-forming auxiliary compounds and do not precipitate. Through such a reaction, the method according to one aspect of the present invention can separate out an optically active compound from a stereoisomer mixture. In contrast, when one molecule of the compound of formula (2) reacts with one molecule of the chiral auxiliary to form a salt, the chiral division to be achieved in the present invention is not achieved.

In one aspect of the present invention, the equivalence ratio of the stereoisomer mixture to the chiral auxiliary may be an equivalent ratio to react the R-type or S-type two molecules of the compound having the structure of formula (2) per one chiral auxiliary .

In one aspect of the invention, the equivalence ratio of the chiral auxiliary to one equivalent of the stereoisomeric mixture may be 0.10 to 0.5 equivalents.

In one aspect of the present invention, the equivalent ratio of the chiral auxiliary is at least 0.01 equivalent, at least 0.05 equivalent, at least 0.1 equivalent, at least 0.1 equivalent, at least 0.2 equivalent, at least 0.25 equivalent, at least 0.3 equivalent , Equal to or greater than 0.35 equivalents, equal to or greater than 0.4 equivalents, equal to or greater than 0.45 equivalents, equal to or greater than 0.5 equivalents, equal to or greater than 0.55 equivalents, or equal to or greater than 0.6 equivalents, equal to or less than 0.6 equivalents, equal to or less than 0.5 equivalents, equal to or less than 0.5 equivalents, equal to or less than 0.45 equivalents, 0.3 equivalent or less, 0.25 equivalent or less, 0.2 equivalent or less, 0.15 equivalent or less, 0.10 equivalent or less, 0.05 equivalent or less, or 0.01 equivalent or less.

In one aspect of the invention, the equivalence ratio of the salt-forming auxiliary compound to one equivalent of the stereoisomeric mixture may be 0.50 to 1.5 equivalents.

Specifically, the equivalence ratio of the salt-forming auxiliary compound to one equivalent of the stereoisomeric mixture is 0.5 equivalents or more, 0.55 equivalents or more, 0.6 equivalents or more, 0.65 equivalents or more, 0.7 equivalents or more, 0.75 equivalents or more, 0.8 equivalents or more, At least 1.15 equivalents, at least 1.15 equivalents, at least 1.0 equivalents, at least 1.0 equivalents, at least 1.1 equivalents, at least 1.15 equivalents, at least 1.2 equivalents, at least 1.25 equivalents, at least 1.3 equivalents, at least 1.35 equivalents, at least 1.4 equivalents, at least 1.45 equivalents, 1.5, 1.5, 1.5, 1.5, 1.45, 1.4, 1.35, 1.3 or less, 1.25 or less, 1.2 or less, 1.15 or less, Not more than 1.1 equivalents, not more than 1.05 equivalents, not more than 1.0 equivalents, not more than 0.95 equivalents, not more than 0.9 equivalents, not more than 0.85 equivalents, not more than 0.8 equivalents, not more than 0.75 equivalents, not more than 0.7 equivalents, not more than 0.65 equivalents, not more than 0.60 equivalents, 0 equivalent or less.

In one aspect of the present invention, when using a salt-forming auxiliary compound in combination with a chiral auxiliary, it is preferred that, for one equivalent of the stereoisomeric mixture, the chiral auxiliary is combined in a lesser equivalent ratio as compared to the salt- Higher optical purity can be obtained.

In one aspect of the present invention, the equivalent ratio of the chiral auxiliary and the salt-forming auxiliary compound to one equivalent of the stereoisomeric mixture may be 0.6 to 2.0 equivalents. Specifically, the equivalent ratio of the chiral auxiliary and the salt-forming auxiliary compound may be the sum of the equivalence ratios of the chiral auxiliary and salt-forming auxiliary compound described above.

In one aspect, the invention may relate to a stereoisomer of a compound having an enantiomeric excess of 96% to 99%, obtained by fractionation from a stereoisomeric mixture by a method according to one aspect of the present invention.

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

In one aspect of the present invention, an asymmetric carbon atom refers to a carbon atom in which a carbon atom in the molecule is bonded to four different atoms, atoms or functional groups. In the case of a compound containing such an asymmetric carbon atom, it has a photoconductive or optical isomer.

In one aspect of the present invention, a stereoisomeric mixture is an optically active isomeric compound, which may mean a mixture of two enantiomers, wherein the mixing ratio may be 1: 1 (in this case, it is a racemic mixture ), Or the mixing ratio may correspond to a ratio of an integer between 1:10 and 10: 1. In one aspect of the present invention, the stereoisomeric mixture may be an artificially synthesized mixture or a mixture in which the ratio of the R-type optical isomer to the S-type optical isomer is unknown. According to the method of the present invention, the ratio of the optical isomer of either R or S can be remarkably increased, so that the optical isomer of the desired form can be obtained purely regardless of the ratio of the mixture. Specifically, the stereoisomer mixture may have a mixing ratio of R-type and S-type optical isomers of 1: 1.

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

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

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

In one aspect of the present invention there is provided a process for the preparation of (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino- phenyl) (PAC-14028) corresponds to CAS No. 1005168-10-4 and corresponds to a molecular weight of 491.47 Da.

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

INT-2 (N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide) with a chiral auxiliary and a salt-forming auxiliary compound;

Adding 10 times the amount of polar quantum solvent to the mixture to the weight of INT-2;

Refluxing the mixed solution to which the polar protic solvent has been added for 1 to 4 hours at 30 ° C to 70 ° C;

Cooling the stirred mixture;

Filtering the solid resulting from cooling to obtain INT-3 chiral acid salt.

In one aspect of the present invention, the cooling may be cooling to 15 to 30 캜 after reflux.

In one aspect of the invention, the cooling is performed at a temperature of at least 10 캜, at least 15 캜, at least 20 캜, at least 22 캜, at least 24 캜, at least 25 캜, at least 26 캜, at least 28 캜, at least 30 캜, 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 Lt; / RTI >

In one aspect of the present invention, the method may further comprise the step of separating the chiral acid from the obtained INT-3 chiral acid salt, and more particularly, the step of separating INT-3 chiral acid salt After adding 5 times the weight of water and 2 equivalents of 28 vol.% Aqueous ammonia solution, the suspension obtained by stirring for 20 to 50 minutes was filtered, and the excess water was removed under reduced pressure vacuum to obtain R type or S type Lt; RTI ID = 0.0 > optical isomer. &Lt; / RTI >

In one aspect, the present invention may relate to a chiral resolution method of a stereoisomeric mixture comprising the steps of:

(1) mixing a stereoisomeric mixture of a compound having an amine group bonded to an asymmetric carbon atom with a chiral auxiliary and a salt-forming auxiliary compound.

In one aspect of the present invention, the chiral auxiliary in the step (1) is selected from the group consisting of 2,3-dibenzoyl-tartaric acid, O, O'-di- p -toluoyltartaric acid, their stereoisomers, Lt; / RTI >

In one aspect of the present invention, in the step (1), the salt-forming auxiliary compound may be at least one selected from the group consisting of mandelic acid, camphorsulfonic acid, a stereoisomer thereof, and a combination thereof.

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

In one aspect of the present invention, the solvent can be polar protons for daily use.

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

In one aspect of the present invention, the stirring in the step (3) is carried out for at least 30 minutes, at least 1 hour, at least 1 hour, at least 30 minutes, at least 2 hours, at least 2 hours, at least 30 minutes, at least 3 hours, Less than 3 hours, less than 3 hours, less than 2 hours, less than 30 minutes, less than 2 hours, less than 5 hours, less than 4 hours, less than 4 hours, less than 3 hours, less than 30 minutes, less than 3 hours , 1 hour 30 minutes or less, 1 hour or less, or 30 minutes or less.

In one aspect of the present invention, the stirring in step (3) is performed at a temperature of 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, Deg.] C or less, or 70 [deg.] C or less, 65 [deg.] C, 60 deg. C, 55 deg. Or less.

In one aspect of the present invention, the method may further comprise cooling the mixture of step (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 a diastereomeric salt of the compound. Specifically, in one aspect of the invention, the diastereomeric salt of the compound may be an INT-3 diastereomeric salt.

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

In one aspect of the present invention, the step (6) may include 1) a step of injecting water and an aqueous ammonia solution into the diastereomeric salt of INT-3. Specifically, in one aspect of the present invention, the water in step (6) is at least two times, three times, four times, five times, six times, or more than seven times the weight ratio of INT-3 diastereomer salt Or less than seven times, not more than six times, not more than five times, not more than four times, three times or less, or two times or less. More specifically, in one aspect of the present invention, in step (6), the aqueous ammonia solution contains 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 less, 40 vol% or less, 36 vol% or less, 32 vol% or less, 28 vol% or less, 24 vol% or less, or 20 vol% or less. Specifically, in one aspect of the present invention, in step (6), the aqueous ammonia solution is added in an amount of 0.5 equivalents or more, 1 equivalent or more, 1.5 equivalents or more, 2 equivalents or more, 2.5 equivalents or more, 3 equivalents or more, 3 equivalents or less, 2.5 equivalents or less, 2 equivalents or less, 1.5 equivalents or less, 1 equivalent or less, or 0.5 equivalents or less.

In one aspect of the present invention, the step (6) may further include a step of stirring the mixed solution after step 2). Specifically, in one aspect of the present invention, stirring in the step (6) is performed for 5 minutes or more, 10 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, 50 minutes or more, 60 minutes or more or 70 minutes or more Stirring for 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 present invention, the step (6) may further comprise the step of 3) filtering the suspension obtained by stirring.

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

In one aspect, the present invention provides a method of chiral separation of a stereoisomeric mixture of a compound having the structure of Formula 1 by a method according to one aspect of the present invention. And converting the segmented stereoisomer to a compound having the structure of Formula 3a or 3b,

[Chemical Formula 3]

(3b)

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are independently selected from the group consisting of H; -NH ₂ ; A C _1-6 alkyl group; A C _2-6 alkenyl group; A C _2-6 alkynyl group; And halogen, and < RTI ID = 0.0 >

The above R ₁ and R ₂ may relate to a method for producing a compound having the structure of the formula (3a) or (3b) having different substituents. Such a manufacturing method is specifically described in Korean Patent Application No. 10-2009-7004333.

In one aspect of the present invention, the compound having the structure of Formula (3a) is (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino- phenyl) (PAC-14028), and the compound having the structure of Formula 1 is N- {4 - [(1R / S) -1 -Aminoethyl] -2,6-difluorophenyl} methanesulfonamide. &Lt; / RTI >

In one aspect of the present invention, the step of converting the segmented stereoisomers into a compound having the structure of formula (3a) or (3b) comprises reacting N- {4 - [(1R) -1- aminoethyl] -2,6-difluoro (INT-3) and 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (INT-7) .

The stereoisomers separated by the method according to one aspect of the present invention can be used as an intermediate in the preparation of the novel drug described in the application by reacting with the substance described in Korean Patent Application No. 10-2009-700433. Accordingly, in one aspect, the present invention provides a method for producing a novel drug as described in Korean Patent Application No. 10-2009-700433 using a separated stereoisomer according to one aspect of the present invention, or a method for producing Lt; / RTI >

In one aspect, the present invention provides a process for preparing (R) -N- [1- (3,5-difluoro-4- Methanesulfonylamino-phenyl) -ethyl] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide.

In one aspect, the present invention provides a process for the preparation of (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino- phenyl) The present invention 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.

In one aspect, the present invention provides a process for the preparation of (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino- phenyl) -ethyl] -3- Inflammatory disease of the joints, including, for example, inflammatory bowel disease, inflammatory bowel disease, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, (IBS) and inflammatory bowel disease (IBD), gastroesophageal reflux disease (IBD), gastroesophageal reflux disease (IBD), gastroesophageal reflux disease Inflammation of the eye or mucous membrane, auditory hypersensitivity, tinnitus, vestibular hypersensitivity, episodic vertigo, epilepsy, epilepsy, vomiting, diarrhea, Myocardial ischemia, hair follicles, hair loss, 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 present invention, the pain is selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-surgical pain, toothache, fibrotic tissue, myofascial pain syndrome, back pain, migraine and other types of headache It may be a disease of choice or pain associated with the disease.

In one aspect, the present invention may relate to an optical resolution agent comprising a chiral auxiliary and a salt-forming auxiliary compound.

In one aspect of the present invention, the optical resolving agent may comprise 0.10 to 0.5 equivalent of chiral auxiliary to 1 equivalent of the stereoisomer mixture to be optically resolved.

In one aspect of the present invention, the optical resolving agent may comprise 0.75 to 1.5 equivalents of a salt-forming auxiliary compound for one equivalent of the stereoisomer mixture to be optically resolved.

In one aspect, the present invention relates to a chiral auxiliary; And a salt-forming auxiliary compound.

In one aspect of the invention, the chiral auxiliary may be 0.10 to 0.5 equivalents based on one equivalent of the stereoisomer mixture to be optically resolved.

In one aspect of the invention, the salt-forming auxiliary compound may be 0.75 to 1.5 equivalents to one equivalent of the stereoisomeric mixture to be optically resolved.

In one aspect of the invention, the kit may further comprise instructions for use of the chiral auxiliary and the salt-forming auxiliary compound.

In one aspect of the present invention, the instructions may include that the chiral auxiliary is used in an amount of 0.10 to 0.5 equivalent to 1 equivalent of the stereoisomer mixture to be optically resolved.

In one aspect of the present invention, the instructions may include that the salt-forming auxiliary compound be used in an amount of 0.75 to 1.5 equivalents per equivalent of the stereoisomer mixture to be optically resolved.

In one aspect of the present invention, the instructions for use may include that the chiral auxiliary and the salt-forming auxiliary compound are mixed with a stereoisomeric mixture in a polar protic solvent when used.

In one aspect of the present invention, the instructions for use may describe a method for chiral resolution of a stereoisomeric mixture according to one aspect of the present invention.

Hereinafter, the present invention will be described with reference to the following examples and test examples. The examples and the test examples are for illustrating the present invention in more detail, and the scope of the present invention is not limited to the range of the following examples. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope of the invention.

[Comparative Test Example 1] Measurement of optical purity by the conventional asymmetric synthesis method

The conventional asymmetric synthesis method was conducted as shown in the following reaction formula (2).

[Reaction Scheme 2]

(1 eq.) Was added dropwise to a solution of N- {2,6-difluoro-4- [1- (2-methyl- propane- 2-sulfinylamino) -ethyl] -phenyl} -methanesulfonamide (10 equivalents) of tetrahydrofuran (THF) (20 ml), and the solution was further dissolved with NaBH ₄ (4 equivalents). Then, the reaction was carried out at the temperature shown in Table 1 for 10 hours . Then it was added dropwise until hydrogen gas to CH ₃ OH is no longer 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) -Methanesulfonamide. &Lt; / RTI > 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 from acetone to give (R) -N- [4- (1-amino-ethyl) -2,6-difluoro-phenyl] -methanesulfonamide, HCl salt.

The thus obtained salt was subjected to the same process as that of the following test example, and its enantiomer excess was measured and is shown in Table 1 below.

Comparative Example NaBH ₄ < SEP > ee% (R-isomer) 1-1 -48 96.2 1-2 -30 95.4 1-3 -20 95.2 1-4 -10 94.9 1-5 0 degrees 94.2

According to the conventional method, in order to obtain an optical activity of 96% or more, the temperature of -40 ° C or lower should be maintained for 10 hours as shown in Table 1. However, according to the present invention, By a simple process. Therefore, it can be judged that the method of the present invention is significantly more economical than the conventional method. Further, when such a reaction is scaled up on a plant basis, it is much easier to control the temperature to be maintained at 50 ° C than to maintain the temperature of -40 ° C for 10 hours, The scale of the reaction can be easily expanded.

In addition, since the conventional method uses 2 to 4 equivalents of sodium borohydride, excessive explosive hydrogen is generated during the reaction termination process and heat is generated, which is a process involving a very dangerous reaction . On the contrary, the present invention shows a heterogeneous effect capable of obtaining commercially available 96% optically active stereoisomers without involving a dangerous process such as generation of explosive hydrogen or generation of heat .

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

[Comparative Test Example 2] Measurement of optical purity when separated using only a single optical resolving agent

According to the preparation method described in Bioorganic & Medicinal Chemistry (15 (18), 6043-6053; 2007), N- [4- (1-aminoethyl) -2,6- difluorophenyl] -methanesulfonamide R and S isomers) were prepared. The thus prepared N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide and the optical resolving agent described in Tables 2 and 3 were mixed in an amount of 1 equivalent each. To this mixed mixture was added 10 times the amount of solvent (different solvent according to the following table) to the weight of N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide . The solvent-added mixed solution was refluxed at 50 캜 for 3 hours and then cooled to 25 캜. The resulting solid was filtered through a Buchner funnel to give the respective N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide chiralate. The thus obtained salt corresponds to a salt which has been separated once.

The thus-obtained N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide salt thus obtained was added to the mixture in the same manner as described above, and the mixture was refluxed After cooling and filtration were repeated once and twice, respectively, to obtain N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide salt &Lt; / RTI >

To each of the thus obtained N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide chiral acid salt, 5 parts by weight of water and 2 parts by weight of 28 vol% , Stirred for 30 minutes, filtered through a Buchner funnel and the excess water was removed in vacuo to give N- [4 - [( 1R ) -1-aminoethyl] -2,6-difluoro Phenyl] -methanesulfonamide or N- [4 - [( 1S ) -1-aminoethyl] -2,6-difluorophenyl] -methanesulfonamide (INT-3).

Optical purity (enantiomer excess) was analyzed on a chiral HPLC column (Shiseido Chiral CD-Ph 4.6 mm x 250 mm, 5 m) for INT-3 thus obtained. The optical purity (enantiomeric excess, ee%) of each chiral acid salt was measured using a Waters e2695 Alliance HPLC under the following conditions: a 0.5 mol / L sodium perchlorate / methanol mixture (75 vol% , And was calculated by Equation (1). The yield of the reaction was also calculated by the following equation (2). The yields were calculated only for the three separations which yielded the highest optical activity.

The measurement results are shown in Tables 2 and 3 below.

1. Column temperature = 35 DEG C

2. Flow rate = 0.5 ml / min,

3. Detection = 220 nm

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

[Equation 1]

&Quot; (2) "

- actual yield: the amount of product actually obtained

- theoretical gain: the maximum mass of the product obtained from the reactants of a given mass

Comparative Example
Chiral Chiral auxiliary
The solvent
% ee (R-type optical isomer) Yield at 3 times separation
One time separation Separate twice Three times separation 2-1
Benzoyl-D-tartaric acid ((+) - 2,3-di-benzoyl-D-tartaric acid

Water (H ₂ O) 40.1 77.5 91 15 2-2 Methanol 68.4 84.2 97 9 2-3 ethanol 44.2 78.4 94 11 2-4 Isopropyl alcohol 36.9 68.1 92.1 17 2-5 Butanol 24.7 56.9 88.0 17

Comparative Example
Chiral Chiral auxiliary
The solvent
% ee (R-type optical isomer) Yield at 3 times separation
One time separation Separate twice Three times separation 3-1
O, O'-di-para-toluoyl-D-tartaric acid (O, O'-

Water (H ₂ O) 38 71.5 75.4 16 3-2 Methanol 63.2 79.2 96.1 4 3-3 ethanol 41.2 71.5 91 10 3-4 Isopropyl alcohol 35.6 62.3 89.2 15 3-5 Butanol 21.5 49.3 80.0 14

According to Tables 2 and 3, when dibenzoyltartaric acid or di-toluoyltartaric acid alone was used, the optical isomers of higher purity could be obtained as the number of times of separation was increased, and in particular, when methanol and ethanol were used, The highest. However, the purity was not high when not separated more than three times, and these values correspond to purity which is below 96% which is considered to be commercially available.

In the case of using dibenzoyltartaric acid or di-toluoyltartaric acid alone, the yield of the isomer was very low, which was less than 20%, regardless of the solvent.

[Test Example 1] Measurement of optical purity according to kind and mixing ratio of chiral auxiliary and salt-forming auxiliary compound

According to the preparation method described in Bioorganic & Medicinal Chemistry (15 (18), 6043-6053; 2007), N- [4- (1-aminoethyl) -2,6- difluorophenyl] -methanesulfonamide R and S isomers) were prepared. One equivalent of the thus prepared N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide was reacted with the chiral auxiliary and the salt-forming auxiliary compound described in Tables 4 to 8 Were mixed in the equivalent amounts shown in the table. To this mixed mixture was added 10 times each solvent (different solvent according to Tables 4 to 8 below) to the weight of the methanesulfonamide compound. The solvent-added mixed solution was refluxed at 50 캜 for 3 hours and then cooled to 25 캜. The solid resulting from cooling was filtered through a Buchner funnel to give each of the INT-3 chiral acid salts.

To each of the thus obtained N- [4- (1-aminoethyl) -2,6-difluorophenyl] -methanesulfonamide salt was added 5 parts by weight of water and 2 equivalents of a 28% by volume aqueous ammonia solution, The suspension obtained by stirring for 30 minutes was filtered with a Buchner funnel and the excess water was removed under reduced pressure in vacuo to obtain N- [4 - [( 1R ) -1-aminoethyl] -2,6-difluorophenyl ] Methane sulfonamide or N- [4 - [(1S) -1-aminoethyl] -2,6-difluorophenyl] -methanesulfonamide (INT-3).

Optical purity (enantiomer excess) was analyzed on a chiral HPLC column (Shiseido Chiral CD-Ph 4.6 mm x 250 mm, 5 m) for INT-3 obtained as described above. The optical purity of each chiral acid salt was measured using a Waters e2695 Alliance HPLC under the following conditions: a 0.5 mol / L sodium perchlorate / methanol mixture (75 vol%: 25 vol%) was used as the mobile phase.

These measurement results are shown in Tables 4 to 8 below. Table 4 shows the results of experiments on the optical purity and yield of INT-3 depending on the optical activity of mandelic acid, one of the salt-forming auxiliary compounds. Table 5 shows the results of using 2,3-dibenzoyltartaric acid and mandelic acid as the respective equivalents. Table 6 shows the results in the case where 2,3-dibenzoyltartaric acid and camphorsulfonic acid were used and their equivalents. Table 7 shows the results when using di-para-toluoyltartaric acid and mandelic acid, respectively. Table 8 shows the results when using ditoluoyltartaric acid and camphorsulfonic acid as the respective equivalents. Each table shows the results of analysis of the chiral acid salt obtained by different solvents according to this embodiment.

1. Column temperature = 35 DEG C

2. Flow rate = 0.5 ml / min,

3. Detection = 220 nm

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

Optical purity was calculated according to Equation (1) above, and reaction yield was calculated according to Equation (2).

In addition, the camphorsulfonic acid and mandelic acid used in the test, 2,3-dibenzoyl-tartaric acid and O, O'-di- p -toluoyl-tartaric acid were commercially purchased and used in Sigma Aldrich.

Example Combination of chiral auxiliary and salt-forming auxiliary compound (unit: equivalent) The solvent ee% (R-type optical isomer)
yield(%) (+) - 2,3-dibenzoyl-D-tartaric acid Manderic acid D type D type L type D + L type
(Equivalent ratio) Example 1-1

0.25

1.0

water 88.0 41 Methanol 99.3 16 ethanol 98.5 25 Isopropyl alcohol 99.1 41 Examples 1-2

0.25

1.0

water 88.1 40 Methanol 99.4 15 ethanol 98.9 24 Isopropyl alcohol 99.2 42 Example 1-3

0.25

1.0

water 88.2 41 Methanol 99.4 17 ethanol 98.9 24 Isopropyl alcohol 99.1 42

Example
Combination of chiral auxiliary and salt-forming auxiliary compound (unit: equivalent ) The solvent
ee% (R-type optical isomer)

yield(%) (+) - 2,3-dibenzoyl-D-tartaric acid D or L-mandelic acid 2-1 0.25 One water

88.2 40 2-2 0.35 One 84.5 45 2-3 0.5 One 56.3 21 2-4 One One 30 80 2-5 0.25 One Methanol

99.4 15 2-6 0.35 One 98.1 16 2-7 0.5 One - - 2-8 One One - - 2-9 0.25 One ethanol

98.9 24 2-10 0.35 One 98.1 25 2-11 0.5 One 66.4 40 2-12 One One 10 71 2-13 0.25 One Isopropyl alcohol

99.1 41 2-14 0.35 One 98.7 42 2-15 0.5 One 97.4 21 2-16 One One 15 82 2-17 0.25 0.75 99.1 42 2-18 0.25 1.5 99.2 38 2-19 0.35 0.75 98.7 40 2-20 0.35 1.5 98.6 32 2-21 0.5 0.75 96.9 24 2-22 0.5 1.5 96.1 16

* In Mandel's case, the results were the same regardless of the type D or L type.

Example
Combination of chiral auxiliary and salt-forming auxiliary compound (unit: equivalent) The solvent
ee% (R-type optical isomer)

yield(%) (+) - 2,3-dibenzoyl-D-tartaric acid R or S-camphorsulfonic acid ((R, S) -10-Camphorsulfonic acid) 3-1 0.25 One water

88.5 39 3-2 0.35 One 84.7 42 3-3 0.5 One 60.0 19 3-4 One One 32 75 3-5 0.25 One Methanol

99.2 13 3-6 0.35 One 98.5 16 3-7 0.5 One 97.3 9 3-8 One One - - 3-9 0.25 One ethanol

98.5 21 3-10 0.35 One 98.5 24 3-11 0.5 One 66.5 39 3-12 One One 15 68 3-13 0.25 One Isopropyl alcohol

99.0 40 3-14 0.35 One 98.9 41 3-15 0.5 One 97.1 25 3-16 One One 16 81 3-17 0.25 0.75 98.3 40 3-18 0.25 One 98.8 38 3-19 0.25 1.5 99.1 38 3-20 0.35 0.75 97.1 41 3-21 0.35 One 97.9 39 3-22 0.35 1.5 98.7 34

In the case of camphorsulfonic acid, the results were the same regardless of the R type and the S type.

Example
Combination of chiral auxiliary and salt-forming auxiliary compound (unit: equivalent) The solvent
ee% (R-type optical isomer)

yield(%) (+) - O, O'-di- p -toluoyl-D-tartaric acid D or L-mandelic acid 4-1 0.25 One water

79.2 38 4-2 0.35 One 75.3 41 4-3 0.5 One 49.1 22 4-4 One One 21 79 4-5 0.25 One Methanol

97.5 14 4-6 0.35 One 96.2 15 4-7 0.5 One - - 4-8 One One - - 4-9 0.25 One ethanol

97.1 21 4-10 0.35 One 96.5 24 4-11 0.5 One 56 39 4-12 One One 11 68 4-13 0.25 One Isopropyl alcohol

98.1 38 4-14 0.35 One 96.9 37 4-15 0.5 One 96.1 21 4-16 One One 14 79 4-17 0.25 0.75 98 40 4-18 0.25 1.5 98.5 35 4-19 0.35 0.75 96.5 39 4-20 0.35 1.5 97 31 4-21 0.5 0.75 96.1 24 4-22 0.5 1.5 96.5 14

Example
Combination of chiral auxiliary and salt-forming auxiliary compound (unit: equivalent) The solvent
ee% (R-type optical isomer)

yield(%) (+) - O, O'-di- p -toluoyl-D-tartaric acid R or S-camphorsulfonic acid ((R, S) -10-Camphorsulfonic acid) 5-1 0.25 One water

79.0 35 5-2 0.35 One 77.2 39 5-3 0.5 One 51.2 20 5-4 One One 21.5 75 5-5 0.25 One Methanol

98.1 16 5-6 0.35 One 96.5 15 5-7 0.5 One 97.0 8 5-8 One One - - 5-9 0.25 One ethanol

97.5 22 5-10 0.35 One 96.1 23 5-11 0.5 One 61 35 5-12 One One 13 71 5-13 0.25 One Isopropyl alcohol

98.2 34 5-14 0.35 One 97.0 35 5-15 0.5 One 96.5 25 5-16 One One 17 75 5-17 0.25 0.75 96.5 38 5-18 0.25 One 97.1 35 5-19 0.25 1.5 97.5 34 5-20 0.35 0.75 96.5 39 5-21 0.35 One 97.9 39 5-22 0.35 1.5 97.1 34

According to the results shown in Table 4, it was confirmed that the optical activity of mandelic acid corresponding to the acid forming the soluble salt in the optical resolution was not affected. Specifically, when D-type L-type mandelic acid is mixed with D-type and L-type, the results are almost the same. It was confirmed that it is a tartaric acid derivative such as dibenzoyltartaric acid which plays an important role in optical resolution.

According to the results shown in Tables 5 to 8, when using diacyltartaric acid, N - [4- (1-aminoethyl) -1,2,3,4-tetrahydroisoquinoline was used as a polar solvent in water, methanol, ethanol and isopropyl alcohol, 2-yl) -phenyl] -methanesulfonamide and 1 equivalent of diacyltartaric acid (molecule) form a salt.

According to Tables 5 to 8, when the equivalents of mandelic acid and camphorsulfonic acid were kept constant, the equivalent purity of diacyltartaric acid was 0.25 equivalent, 0.35 equivalent, 0.5 equivalent, and 1 equivalent, 0.35 equivalents and 0.5 equivalents in the order of 1 equiv, whereas the optical purity of 1 equiv.

Thus, in this result, 2 equivalents of N - [(R) -4- (1-aminoethyl) -phenyl] -methanesulfonamide was obtained under the conditions of water, methanol, ethanol and isopropyl alcohol as the polar protic solvents described in the above table Molecule) and 1 equivalent of diacyltartaric acid (molecule) form a salt and are selectively separated.

Specifically, according to Tables 5 and 6, in which 2,3-dibenzoyl-D-tartaric acid was used with mandelic acid or camphorsulfonic acid, the optical purity was as low as 89% ee or less when the solvent was water and in the case of methanol and ethanol, Showed a high optical purity of 96% ee or more in the case of 0.25 equivalent and 0.35 equivalent, but the yield was 25% or less. Even in this case, the yield is two times higher than that in Table 2 using only 2,3-dibenzoyl-D-tartaric acid alone. Particularly, in the case where the solvent was methanol, the use of mandelic acid did not cause separation when 0.5 equivalents of dibenzoyl-D-tartaric acid was used, but it was separated when camphorsulfonic acid was used. When the solvent was isopropyl alcohol, 0.25 equivalent, 0.35 equivalent, and 0.5 equivalent of tartaric acid were used, indicating a high optical purity of 96% ee or more and a yield of 20% or more, especially 0.25 equivalent and 0.35 equivalent of tartaric acid , The yield was 40% or more and could be obtained at a high yield.

Based on these results, it was confirmed that the equivalents of tartaric acid in isopropyl alcohol were fixed and the equivalents of mandelic acid or camphorsulfonic acid were different from those of Examples 2-17 to 2-22 and Examples 3-17 to 3-22 do. According to these results, it was confirmed that when the equivalence of tartaric acid is 0.5 or less, the equivalent of mandelic acid or camphorsulfonic acid is 0.75 to 1.5 equivalent, all of R isomers can be obtained with high optical purity of 96% ee or more and high yield Respectively. Especially, in Examples 2-17, isomers were obtained with a high optical purity of 96% ee or more and a yield of 42%, which is the highest yield.

Also, according to Tables 7 and 8 using O, O'-di- p -toluoyl-tartaric acid and mandelic acid or camphorsulfonic acid, optical purity was lower than 80% ee when the solvent was water and methanol / ethanol In the case of 0.25 equivalents and 0.35 equivalents of tartaric acid, high optical purity of 96% ee or more was obtained, but the yield was less than 25%. Even in this case, the yield is two times higher than that in Table 3 using only O, O'-di- p -toluoyl-tartaric acid alone. In addition, when camphorsulfonic acid was used as in the case of dibenzoyl-D-tartaric acid, optical separation took place when 0.5 equivalent of di-para-toluoyltartaric acid was used in a methanol solvent. When the solvent was isopropyl alcohol, 0.25 equivalent, 0.35 equivalent, and 0.5 equivalent of tartaric acid were used, indicating a high optical purity of 96% ee or more and a yield of 20% or more, especially 0.25 equivalent and 0.35 equivalent of tartaric acid , The yield was 34% or more and could be obtained at a high yield.

According to the results of Examples 4-17 to 4-22 and 5-17 to 5-22 in which the equivalence of tartaric acid in isopropyl alcohol was fixed and the equivalents of mandelic acid or camphorsulfonic acid were different, the equivalent of tartaric acid was 0.5 , It was confirmed that when the equivalent of mandelic acid or camphorsulfonic acid is 0.75 to 1.5 equivalents, the R-isomer can be obtained with high optical purity of 96% ee or more and high yield. Particularly, in Examples 4-17, isomers were obtained with a high optical purity of 96% ee or more and a yield of 40%, which is the highest yield.

According to the above results, it was confirmed that when the equivalent of diacyltartaric acid is 0.25 to 0.5 and the equivalent of mandelic acid or camphorsulfonic acid is 0.75 to 1.5, an R-isomer having a high optical purity of 96% ee or more can be obtained , And isomer was obtained at a higher level of yield, especially when the solvent is isopropyl alcohol. Further, when the equivalent of diacyltartaric acid is 0.25 to 0.35 and when the solvent is isopropyl alcohol, when reacted with mandelic acid or camphorsulfonic acid in the range of 0.75 to 1.5 equivalents, an optical activity of 96% ee or more and a yield of 30% or more Lt; / RTI >

These results indicate that when 2,3-dibenzoyltartaric acid or O, O'-di- p -toluoyltartaric acid is an L-isomer, the S-form N- {4- [(1S) 2,6-difluorophenyl} methanesulfonamide, which would be obvious to those of ordinary skill in the art.

Therefore, according to the above results, the method according to one aspect of the present invention can obtain R-type or S-type optical isomers having high optical purity.

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

(R) -N- [1- (4-fluorophenyl) -1H-imidazol-1-yl] (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide was prepared according to Korean Patent Application 10 -2009-7004333.

Specifically, a mixture of N- {4 - [(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide, HCl salt (62 mg, 0.22 mmol) -Pyridin-3-yl) -acrylic acid (56 mg, 0.22 mmol) and crystallizing from ether to give 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

Accordingly, the R-isomer of the compound having the structure of formula (1) divided according to one aspect of the present invention can be prepared by preparing a variety of novel compounds capable of acting as TRPV1 antagonists by the substance or method described in Korean Patent Application No. 10-2009-7004333 And the like.

Formulation examples of compositions according to one embodiment of the present invention are described below, but may be applied to various other formulations, which are not intended to be limiting but merely illustrative of the invention.

[Formulation Example 1] Amorphous optical resolving agent

0.1 to 0.5 equivalents of 2,3-dibenzoyltartaric acid and O, O'-di- p -toluoyl-tartaric acid with respect to one equivalent of the stereoisomeric mixture; And 0.75 to 1.5 equivalents of mandelic acid and camphorsulfonic acid.

[Formulation Example 2]

0.1 to 0.5 equivalents of 2,3-dibenzoyltartaric acid and O, O'-di- p -toluoyl-tartaric acid with respect to one equivalent of the stereoisomeric mixture; And 0.75 to 1.5 equivalents of at least one of mandelic acid and camphorsulfonic acid.

Claims

As a chiral resolution method of a stereoisomeric mixture,
A stereoisomeric mixture of the compound having the structure of the following formula
(i) a chiral auxiliary and
(ii) an auxiliary salt-forming compound with a polar protic solvent to precipitate an enantiomeric excess of the diastereomeric salt of the compound having the structure of formula (I) and the chiral auxiliary, Including,
[Chemical Formula 1]

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are independently selected from the group consisting of H; -NH ₂ ; A C _1-6 alkyl group; A C _2-6 alkenyl group; A C _2-6 alkynyl group; And halogen, and < RTI ID = 0.0 >
Wherein R ₁ and R ₂ are different substituents.

The method according to claim 1,
Wherein said chiral auxiliary is 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;
Wherein the salt-forming auxiliary compound is at least one selected from the group consisting of mandelic acid, camphorsulfonic acid, their stereoisomers, and combinations thereof.

The method according to claim 1,
The method is further characterized in that the chiral auxiliary is selected from the group consisting of (+) - 2,3-dibenzoyl-D-tartaric acid, (+) - O, O'-di- p -toluoyl- , The R-type optical isomer of the compound of formula (1) is obtained in enantiomeric excess.

The method according to claim 1,
The method is characterized in that the chiral auxiliary is selected from the group consisting of (-) - 2,3-dibenzoyl-L-tartaric acid, (-) - O, O'-di- p- , The S-type optical isomer of the compound of formula (1) is obtained in enantiomeric excess.

The method according to claim 1,
Wherein said salt-forming auxiliary compound is selected from the group consisting of D-mandelic acid, L-mandelic acid, (1R) - (-) - 10- camphorsulfonic acid, (1S) - (+) - 10- camphorsulfonic acid, .

The method according to claim 1,
Wherein said halogen is at least one selected from the group consisting of F, Cl, Br and I.

The method according to claim 6,
R ₁ is a group selected from the group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group,
And R < ₂ > is hydrogen.

8. The method of claim 7,
R ₁ is a methyl group,
R ₃ and R ₇ are hydrogen,
R ₄ , R ₅ , and R ₆ are selected from the group consisting of F, Cl, Br, I, and C _1-6 alkyl groups.

9. The method of claim 8,
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 according to claim 1,
Wherein the polar protic solvent is at least one selected from the group consisting of water, C _1-14 alcohol, isopropyl alcohol, acetic acid, nitromethane, propionic acid, formic acid, and combinations thereof.

11. The method of claim 10,
Wherein the polar protic solvent is at least one selected from the group consisting of water, methanol, ethanol, and isopropyl alcohol.

12. The method of claim 11,
Wherein the polar protic solvent is methanol or isopropyl alcohol.

The method according to claim 1,
Wherein the polar protic solvent is added in an amount to dissolve all of the mixtures.

14. The method of claim 13,
Wherein the polar protic solvent is 5-15 times the total weight of the stereoisomeric mixture.

The method according to claim 1,
(Iii) increasing the temperature of the mixture to between 40 DEG C and 70 DEG C or to the boiling point of the solvent.

16. The method according to any one of claims 1 to 15,
Wherein the equivalence ratio of the chiral auxiliary to one equivalent of said stereoisomeric mixture is 0.10 to 0.5 equivalents.

17. The method of claim 16,
Wherein the equivalence ratio of the chiral auxiliary to one equivalent of said stereoisomer mixture is 0.2 to 0.3 equivalents.

16. The method according to any one of claims 1 to 15,
Wherein the equivalent ratio of salt-forming auxiliary compound to one equivalent of said stereoisomeric mixture is 0.5 to 1.5 equivalents.

19. The method of claim 18,
Wherein the equivalence ratio of salt-forming auxiliary compound to one equivalent of said stereoisomeric mixture is 0.75 to 1.5 equivalents.

16. The method according to any one of claims 1 to 15,
Wherein the equivalent ratio of the chiral auxiliary and salt-forming auxiliary compound to one equivalent of said stereoisomeric mixture is from 0.6 to 2.0 equivalents.

A stereoisomer of a compound of formula (I) having an enantiomeric excess of 96% to 99% obtained by resolution from a stereoisomeric mixture by the process according to claim 16.

22. The method of claim 21,
The stereoisomer can be prepared by reacting N- {4 - [(1R) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide or N- {4- [ , 6-difluorophenyl} methanesulfonamide.

A process for producing a compound having the structure of formula (3a) or (3b)
The method comprises the steps of: chiral splitting a stereoisomeric mixture of a compound having the structure of Formula 1 by a method according to any one of Claims 1 to 16; And
Converting said segmented stereoisomer to a compound having the structure of formula (3a) or (3b)
[Chemical Formula 3]

(3b)

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are independently selected from the group consisting of H; -NH ₂ ; A C _1-6 alkyl group; A C _2-6 alkenyl group; A C _2-6 alkynyl group; And halogen, and < RTI ID = 0.0 >
Wherein R < ₁ > and R < ₂ > have different substituents.

24. The method of claim 23,
The compound having the structure of the above-mentioned formula (3a) can be obtained by reacting (R) -N- [1- (3,5-difluoro-4-methanesulfonylamino- Fluoromethyl-pyridin-3-yl) -acrylamide,
Wherein the compound having the structure of Formula 1 is N- {4 - [(1R / S) -1-aminoethyl] -2,6-difluorophenyl} methanesulfonamide.

24. The method of claim 23,
The step of converting the segmented stereoisomer into a compound having the structure of formula (3a) or (3b) can be carried out by reacting N- [4- [(1R) -1- aminoethyl] -2,6- difluorophenyl} methanesulfonamide -3) and 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (INT-7).

(R) -N- [1- (3,5-Difluoro-4-methanesulfonylamino-phenyl) -ethyl] -methanone having an enantiomeric excess of 96% to 99% -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide.

A chiral auxiliary and a salt-forming auxiliary compound,
Wherein the chiral auxiliary is at least one selected from the group consisting of 2,3-dibenzoyl tartaric acid, O, O'-di- p -toluoyl-tartaric acid, their stereoisomers,
Wherein the salt-forming auxiliary compound is at least one selected from the group consisting of mandelic acid, camphorsulfonic acid, their stereoisomers, and combinations thereof.

28. The method of claim 27,
Wherein the optical resolving agent comprises 0.10 to 0.5 equivalents of a chiral auxiliary with respect to one equivalent of the stereoisomer mixture to be optically resolved.

28. The method of claim 27,
Wherein the optical resolving agent comprises 0.75 to 1.5 equivalents of salt-forming auxiliary compound with respect to one equivalent of the stereoisomeric mixture to be optically resolved.

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;
At least one salt-forming auxiliary compound selected from the group consisting of mandelic acid, camphorsulfonic acid, their stereoisomers, and combinations thereof.

31. The method of claim 30,
Wherein the chiral auxiliary is 0.10 to 0.5 equivalents based on 1 equivalent of the stereoisomer mixture to be optically resolved.

31. The method of claim 30,
The salt-forming auxiliary compound is 0.60 to 1.5 equivalents to 1 equivalent of the stereoisomeric mixture to be optically resolved.

31. The method of claim 30,
Wherein the kit further comprises instructions for use of a chiral auxiliary and a salt-forming auxiliary compound.