HK1237332A1 - Chiral resolution method of n-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives - Google Patents

Description

Chiral resolution method of N- [4- (1-aminoethyl) -phenyl ] -sulfamide derivative

Technical Field

The present disclosure relates to a process for chiral resolution of N- [4- (1-aminoethyl) -phenyl ] -sulfonamide derivatives.

Background

Recently, the demand for stereochemically pure compounds has rapidly increased. An important use of these pure stereoisomers is as synthetic intermediates in the pharmaceutical industry. For example, it is becoming apparent that enantiomerically pure drugs have many advantages over racemic drug mixtures. Advantages generally include fewer side effects and better efficacy of enantiomerically pure compounds [ see, e.g., Stinson, s.c., ChemEng News, 1992, 9/28 th, pages 46-79 ].

For example, triadimenol may be present as four isomers. The (-) - (1S, 2R) -isomer has a stronger activity than the (+) - (1R, 2R) -isomer, and the (-) - (1S, 2S) -isomer has a stronger activity than the- (1R, 2S) -isomer. Of the four isomers of dichlorobutazole, the (1R, 2R) -isomer is known to have greater activity. In addition, for epoxiconazole, the (+) - (2S, 4S) -isomer and the (-) - (2S, 4R) -isomer are known to have a better fungicidal effect than the other isomers.

Therefore, if only one isomer having higher activity can be selectively produced, better effects can be obtained with a smaller amount, and thus, environmental pollution due to the use of chemicals can be reduced. Especially for drugs, if one isomer shows toxicity in the human body, it is very important to selectively prepare only one isomer.

Therefore, in the fields related to medicine, pharmacy and biochemistry, it is a very important subject to prepare an optically pure compound for improving the drug effect or preventing side effects.

However, there are still many Drugs used as racemic compounds with inevitable side effects due to the presence of undesired enantiomers (see, e.g., Nguyen et al, Chiral Drugs: An Overview, int.J.biomed.Sci., 2(2006) 85-100). Several techniques are available for chiral separation on a preparative or analytical scale. However, a great deal of time and effort is required to find a separation technique suitable for the racemate of interest. Even if one successfully resolves the enantiomers, one would face the next difficulty, namely, enabling chiral resolution on an industrial scale.

For example, the efficacy of pure stereoisomers of vanilloid antagonists comprising N- [4- (1-aminoethyl) -phenyl ] -sulfonamide derivatives has been described [ e.g., WO 2008-013414A 1, WO 2007-133637A 2, WO 2007-129188A1, WO 2010-010934A 1 ].

As a method for synthesizing a single isomer of N- [4- (1-aminoethyl) -phenyl ] -sulfonamide derivative, asymmetric synthesis using Ellman's reagent is known. For example, WO 2008-013414 a1, WO 2007-133637 a2, WO2007-129188 a1 and WO 2010-010934 a1 provide a method for obtaining a target stereoisomer by introducing an Ellman reagent and inducing asymmetric reduction using the reagent. However, this method has the disadvantage that low temperature reaction conditions should be maintained to achieve high optical purity (enantiomeric excess,% ee). In addition, the process is hazardous because excess hydrogen and heat are generated when the reaction is terminated. Furthermore, the disposal costs of the excessively generated organic and inorganic wastes are also economically disadvantageous.

Disclosure of Invention

Technical problem

Although asymmetric synthesis of N- [4- (1-aminoethyl) -phenyl ] -sulfonamide derivatives has been reported, a preparation method that can be used on a commercial scale has not been established due to problems in terms of economy and safety. Accordingly, the present disclosure aims to solve the problems of the existing asymmetric synthesis methods and to provide a new method for chiral resolution of stereoisomers into S or R compounds with high optical purity.

Technical scheme

In one aspect, the present disclosure provides a process for resolving N- [4- (1-aminoethyl) -phenyl ] -sulfonamide derivatives of formula (I) into the corresponding compounds with high optical purity by using an O, O' -diacyltartaric acid derivative (one example of a chiral auxiliary agent) and a soluble hydrochloric acid (one example of a salt-forming compound):

in one embodiment, the present disclosure relates to a process for the resolution of (R, S) -N- [4- (1-aminoethyl) -phenyl ] -sulfonamide into N- [4- (1-aminoethyl) -phenyl ] -sulfonamide with high optical purity comprising: (i) (R) -or (S) -N- [4- (1-aminoethyl) ] -sulfonamide diacyl tartrate salt or a solvate thereof having high optical purity is prepared by mixing (R, S) -N- [4- (1-aminoethyl) -phenyl ] -sulfonamide derivative with optically active O, O' -diacyltartaric acid derivative (an example of a chiral auxiliary agent) and soluble hydrochloric acid (an example of a salt-forming compound) in a polar protic solvent, and (ii) the resulting N- [4- (1-aminoethyl) -phenyl ] -sulfonamide salt or a solvate thereof having high optical purity is released by using a base.

According to the process of the present disclosure, N- [4- (1-aminoethyl) -phenyl ] -sulfonamide derivatives can be easily resolved into the corresponding compounds with high optical purity.

N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide is the generic name for a compound having the structure of formula (II):

and are believed to be intermediates useful in the preparation of compounds that act as TRPV1 (transient receptor potential cation channel subfamily V member 1, or capsaicin receptor or vanilloid receptor 1) antagonists.

As can be seen from formula (II), N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide is a chiral compound in which the amine group is bonded to an asymmetric carbon atom (chiral center).

Advantageous effects

According to the chiral resolution method of one aspect of the present disclosure, a stereoisomer mixture, particularly a stereoisomer mixture of a compound in which an amine group is bonded to an asymmetric carbon atom, can be easily chirally resolved into a compound having a high optical purity. The synthesis method provides improved safety and economy compared to the asymmetric synthesis method using Ellman's reagent. Which makes possible chiral resolution with comparable or better optical purity and provides improved economy and environmental friendliness through collection and recovery of the salt. Thus, the method can be advantageously used in the fields of pharmaceuticals and cosmetics requiring chiral resolution of compounds.

In particular, the method according to the present disclosure allows for the efficient preparation of target stereoisomers with comparable or better optical purity compared to existing asymmetric synthesis methods using Ellman's reagent. It is also efficient for large-scale production and offers economic advantages.

Detailed Description

In one aspect, the present disclosure provides a resolution method for a mixture of stereoisomers of a compound,

comprising the step of combining said stereoisomer mixture of the compound with:

(i) a chiral auxiliary; and

(ii) an auxiliary salifying compound is added to the reaction mixture,

thereby precipitating the diastereomeric salt of the chiral auxiliary (i) with the compound. In one aspect, the resolution process involves a chiral resolution process.

In one aspect, the present disclosure provides a process for resolving a mixture of stereoisomers of a compound of formula (I),

comprising the step of mixing said mixture of stereoisomers of the compound of formula (I) in the presence of a solvent with:

(i) a chiral auxiliary; and

(ii) an auxiliary salifying compound is added to the reaction mixture,

thereby precipitating the diastereomeric salt of the chiral auxiliary (I) with the compound of formula (I).

In one embodiment of the present disclosure, the process according to the present invention provides a stereoisomer of the compound of formula (I) in enantiomeric excess, in particular with high optical purity.

The term "enantiomeric excess" in the present disclosure generally includes any increase in the ratio of enantiomers, and thus includes not only an enantiomeric excess as compared to a racemic mixture, but also an increase in one enantiomer relative to another as compared to a mixture in which the ratio of enantiomers is not 1: 1 (as in a racemate). In some embodiments, the term enantiomeric excess specifically corresponds to an enantiomeric excess value ("% ee") of at least 80%, or at least 90%, or at least 95% or at least 96%, or at least 97%, or at least 98%, or at least 99%.

The term "high optical purity" in this disclosure is a term well known in the art. In some embodiments, the term "high optical purity" corresponds to an enantiomeric excess value ("% ee") of at least 80%, or at least 90%, or at least 95% or at least 96%, or at least 97% or at least 98% or at least 99%.

In one aspect, the present disclosure provides a method for chiral resolution of a mixture of stereoisomers, comprising mixing the mixture of stereoisomers with a soluble to hydrochloric acid (one example of a salt former compound) and an optically active O, O' -diacyltartaric acid derivative (one example of a chiral auxiliary).

The term "salt-forming compound" in the present disclosure is not only a compound that resolves a mixture of stereoisomers, but is also a compound that helps to improve the optical purity of a mixture of stereoisomers. The different solubilities of the salts formed with the enantiomers and the chiral auxiliary in the salt-forming compound are used to aid in the resolution of the mixture of stereoisomers. The salt-forming compound may be an acid or a salt thereof capable of dissolving the mixture of stereoisomers to be resolved. Such salt-forming compounds help one enantiomer, which does not form an insoluble salt with the chiral auxiliary, remain soluble, thereby helping to obtain an insoluble salt of the other enantiomer in enantiomeric excess.

In an exemplary embodiment of the present disclosure, the soluble salt-forming acid (an example of a salt former compound) may be selected from mandelic acid, camphorsulfonic acid, stereoisomers thereof, and combinations thereof. The term "chiral auxiliary" in the present disclosure is well known to those skilled in the art, and specifically refers to a chemical compound or unit that is temporarily incorporated into an organic synthesis to control the stereochemical outcome of the synthesis. The chirality of the Chiral auxiliary may predispose the stereoselectivity of one or more subsequent reactions (see, for example, Chiral auxiliary, Wikipedia: http:// en. wikipedia. org/wiki/Chiral _ auxiary). In the present disclosure, the terms chiral auxiliary and chiral acid are used interchangeably.

In an exemplary embodiment of the present disclosure, the chiral auxiliary may be an O, O' -diacyltartaric acid derivative. The chiral auxiliary may be selected from the group consisting of 2, 3-dibenzoyltartaric acid, O' -di-p-toluyltartaric acid, stereoisomers thereof, and combinations thereof.

In an exemplary embodiment of the present disclosure, the 2, 3-dibenzoyl tartaric acid may be (+) -2, 3-dibenzoyl-D-tartaric acid or (-) -2, 3-dibenzoyl-L-tartaric acid (which are optical isomers of each other), and the O, O ' -di-p-toluoyl tartaric acid may be (+) -O, O ' -di-p-toluoyl-D-tartaric acid or (-) -O, O ' -di-p-toluoyl-L-tartaric acid (which are optical isomers of each other). Although the D and L forms of the tartaric acid derivative can be used either alone or in combination, they are preferably used alone without being mixed with each other. When tartaric acid derivatives in the D and L forms are used in combination in a process according to the present disclosure, lower optical purity can be obtained than when either the D or L form is used alone.

In one exemplary embodiment of the present disclosure, the mandelic acid may be D-mandelic acid or L-mandelic acid, which are optical isomers of each other, or a combination thereof, and the camphorsulfonic acid may be (1R) - (-) -10-camphorsulfonic acid or (1S) - (+) -10-camphorsulfonic acid, which are optical isomers of each other, or a combination thereof. As shown in the examples, the optical isomer forms of mandelic acid or camphorsulfonic acid do not have a significant effect on the optical isomer forms of the final product, and when either one of the optical isomers of mandelic acid or camphorsulfonic acid is used alone or in combination, the final product of high optical purity can be obtained.

In one exemplary embodiment of the present disclosure, the mixture of stereoisomers may be a mixture of stereoisomers of a compound having asymmetric carbon atoms. Specifically, in one exemplary embodiment of the present disclosure, the compound having an asymmetric carbon atom may be a compound in which an amine group is bonded. Specifically, in an exemplary embodiment of the present disclosure, the compound may have a substituted or unsubstituted phenyl group bonded to an asymmetric carbon atom, in addition to an amine group. More specifically, in one exemplary embodiment of the present disclosure, the compound having an asymmetric carbon atom may be a compound of formula (I).

In an exemplary embodiment of the present disclosure, R or S optical isomers with high optical purity can be obtained from a mixture of stereoisomers.

In an exemplary embodiment of the present disclosure, when the chiral auxiliary is selected from the group comprising (+) -2, 3-dibenzoyl-D-tartaric acid and (+) -O, O' -di-p-toluoyl-D-tartaric acid and combinations thereof, the R enantiomer may be obtained in high enantiomeric excess.

In an exemplary embodiment of the present disclosure, the S enantiomer may be obtained with high enantiomeric excess when the chiral auxiliary is selected from the group comprising (-) -2, 3-dibenzoyl-L-tartaric acid or (-) -O, O' -di-p-toluoyl-L-tartaric acid and combinations thereof.

In an exemplary embodiment of the present disclosure, the salt-forming compound may be D-mandelic acid, L-mandelic acid, (1R) - (-) -10-camphorsulfonic acid or (1S) - (+) -10-camphorsulfonic acid, or a combination thereof.

In one exemplary embodiment of the present disclosure, the compound in which the amine group is bonded to the asymmetric carbon atom may have the structure of formula (I):

wherein

R₁、R₂、R₃、R₄、R₅、R₆And R₇Each independently selected from H, -NH₂、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Any one of alkynyl and halogen, and

R₁and R₂Are different from each other.

In one exemplary embodiment of the present disclosure, the halogen may be at least one selected from F, Cl, Br and I, particularly selected from F and Cl.

In one exemplary embodiment of the present disclosure, R₁May be one selected from methyl, ethyl, propyl, butyl and pentyl, and R₂May be hydrogen.

In one exemplary embodiment of the present disclosure, R₁May be methyl, R₃And R₇May be hydrogen, and R₄、R₅And R₆May each independently be selected from F, Cl, Br, I and C_1-6One of the alkyl groups.

In one exemplary embodiment of the present disclosure, R₄And R₆May be F, and R₅May be a methyl group.

In an exemplary embodiment of the present disclosure, the compound may be N- {4- [ (1R/S) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide.

In one exemplary embodiment of the present disclosure, the solvent may be added in an amount to achieve complete dissolution of all reactants.

In one exemplary embodiment of the present disclosure, the solvent may be a polar protic solvent.

In an exemplary embodiment of the present disclosure, the polarityThe protic solvent may be selected from water, C_1-14One or more of alcohols, isopropanol, acetic acid, nitromethane, propionic acid, formic acid, and combinations thereof. Specifically, the polar protic solvent may be one or more selected from the group consisting of water, methanol, ethanol, and isopropanol. More specifically, the polar protic solvent may be methanol or isopropanol. More specifically, the polar protic solvent may be isopropanol.

In an exemplary embodiment of the present disclosure, the polar protic solvent may be used in an amount of 5 to 15 times, specifically 7 to 13 times, more specifically 9 to 11 times, more specifically 10 times (i.e., volume [ solvent ]/weight [ stereoisomer ] or (volume/weight)) based on the total weight of the stereoisomer mixture.

In an exemplary embodiment of the present disclosure, the mixing may be performed at 40 ℃ to 70 ℃ or at the boiling point of the solvent or solvent mixture. Mixing may be carried out for 1 to 4 hours. In an exemplary embodiment of the present disclosure, the mixing may be performed by stirring under reflux.

In an exemplary embodiment of the present disclosure, the mixing can be performed at a temperature of at least 30 ℃, at least 40 ℃, more specifically at least 50 ℃ or at the boiling point of the solvent or solvent mixture.

In an exemplary embodiment of the present disclosure, the mixing temperature may be 30 ℃ or higher, 40 ℃ or higher, 50 ℃ or higher, 60 ℃ or higher or 70 ℃ or higher, or 70 ℃ or lower, 60 ℃ or lower, 50 ℃ or lower, 40 ℃ or lower or 30 ℃ or lower. The mixing temperature can be specifically 40 ℃ to 60 ℃, more specifically 45 ℃ to 55 ℃, more specifically 50 ℃.

In an exemplary embodiment of the present disclosure, the mixing time may be 1 hour or more, 2 hours or more, 3 hours or more, 4 hours or more or 5 hours or more, or 6 hours or less, 5 hours or less, 4 hours or less, 3 hours or less, 2 hours or less or 1 hour or less. The mixing time may specifically be 2 to 4 hours, more specifically 2.5 to 3.5 hours, more specifically 3 hours.

In an exemplary embodiment of the disclosure, the process may be carried out by reacting the compound having the structure of formula (I) in a ratio of two molar equivalents of chiral auxiliary agent per one molar equivalent, comprising the R and S optical isomers in the given ratio. In an exemplary embodiment of the present disclosure, the reaction may be carried out according to scheme 1.

[ scheme 1]

According to scheme 1, two molecules of a compound of formula (I) having an optical activity are combined with one molecule of a chiral auxiliary to form an insoluble salt, which can precipitate. In contrast, compounds which are not bound to a chiral auxiliary are dissolved in the salt former compound and therefore do not precipitate. By this reaction, the process according to the present disclosure can resolve a compound with high optical purity from a mixture of stereoisomers. In another aspect, if a compound of formula (I) is combined with one molecule of a chiral auxiliary to form a salt, the chiral resolution required by the present disclosure is not as good as when two molecules are combined.

In an exemplary embodiment of the present disclosure, the molar equivalents of chiral auxiliary to the mixture of stereoisomers may be the molar equivalents of two molecules of the R-or S-form compound having the structure of formula (I) reacted with one molecule of chiral auxiliary.

In an exemplary embodiment of the present disclosure, the molar equivalent ratio of chiral auxiliary to one molar equivalent of the mixture of stereoisomers may be equal to or less than 0.5, from 0.10 to 0.5, from 0.15 to 0.5, from 0.25 to 0.35, or 0.25.

In an exemplary embodiment of the present disclosure, the chiral auxiliary may be used in an amount of 0.01 equivalent or more, 0.05 equivalent or more, 0.10 equivalent or more, 0.15 equivalent or more, 0.2 equivalent or more, 0.25 equivalent or more, 0.3 equivalent or more, 0.35 equivalent or more, 0.4 equivalent or more, 0.45 equivalent or more, 0.5 equivalent or more, 0.55 equivalent or more or 0.6 equivalent or more, or 0.6 equivalent or less, 0.55 equivalent or less, 0.5 equivalent or less, 0.45 equivalent or less, 0.4 equivalent or less, 0.35 equivalent or less, 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 or less or 0.01 equivalent or less per 1 equivalent of the stereoisomer mixture.

In an exemplary embodiment of the present disclosure, the molar equivalent ratio of salt former compound to 1 molar equivalent of the mixture of stereoisomers may be from 0.50 to 1.5, from 0.75 to 1.5, or from 0.75 to 1.0.

Specifically, the salt-forming compound may be used in an amount of 0.5 equivalent or more, 0.55 equivalent or more, 0.6 equivalent or more, 0.65 equivalent or more, 0.7 equivalent or more, 0.75 equivalent or more, 0.8 equivalent or more, 0.85 equivalent or more, 0.9 equivalent or more, 0.95 equivalent or more, 1.0 equivalent or more, 1.05 equivalent or more, 1.1 equivalent or more, 1.15 equivalent or more, 1.2 equivalent or more, 1.25 equivalent or more, 1.3 equivalent or more, 1.35 equivalent or more, 1.4 equivalent or more, 1.45 equivalent or more, 1.5 equivalent or more, 1.55 equivalent or more or 1.6 equivalent or more, or 1.6 equivalent or less, 1.55 equivalent or less, 1.5 equivalent or less, 1.45 or less, 1.4 equivalent or less, 1.35 equivalent or less, 1.3 equivalent or less, 1.2 equivalent or less, 1.5 equivalent or less, 1.45 equivalent or less, 1.1 equivalents or less, 1.05 equivalents or less, 1.0 equivalents or less, 0.95 equivalents or less, 0.9 equivalents or less, 0.85 equivalents or less, 0.8 equivalents or less, 0.75 equivalents or less, 0.7 equivalents or less, 0.65 equivalents or less, 0.6 equivalents or less, 0.55 equivalents or less, or 0.50 equivalents or less.

In an exemplary embodiment of the present disclosure, the molar equivalent ratio of the chiral auxiliary and salt former compound together to 1 molar equivalent of the mixture of stereoisomers may be 0.6 to 2.0, 0.75 to 2.0, 0.8 to 2.0, 1.0 to 1.85, or 1.0 to 1.35. In particular, the molar equivalent ratio of the chiral auxiliary and the salt-forming compound together may be a value that adds the molar equivalents of the chiral auxiliary and the molar equivalents of the salt-forming compound described above.

In an exemplary embodiment of the present disclosure, when the salt-forming compound and the chiral auxiliary are used in combination, higher optical purity can be obtained when the chiral auxiliary is used at a ratio of equivalents less than that of the salt-forming compound per 1 equivalent of the racemic mixture.

In an exemplary embodiment of the present disclosure, there is provided a stereoisomer of a compound having an enantiomeric excess of at least 96%, at least 97%, at least 98%, at least 99%, or 96% to 99% obtained by a process according to the present invention. In another aspect, the present disclosure provides R or S optical isomer compounds prepared by resolving a mixture of stereoisomers according to the methods of the present disclosure.

In an exemplary embodiment of the present disclosure, the stereoisomer may be N- {4- [ (1R) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide or N- {4- [ (1S) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide.

In the context of the present disclosure, an asymmetric carbon atom may refer to a carbon atom that connects four different types of atoms, groups, or functional groups. The compound having an asymmetric carbon atom exhibits optical rotation, optical activity or optical isomerism.

In the context of the present disclosure, a mixture of stereoisomers may refer to a mixture of two optically active enantiomers. The mixing ratio may be 1: 1 (corresponding to the racemic mixture), or more specifically, any ratio of 1: 10 to 10: 1. In the context of the present disclosure, a mixture of stereoisomers may be one or a mixture of synthetic R and S optical isomers with unknown ratios. According to the method of the present disclosure, the ratio of one of R or S optical isomers can be significantly increased, and a target optical isomer having high optical purity can be obtained regardless of the mixing ratio of the mixture. Specifically, the mixture of stereoisomers to be resolved may be a 1: 1 mixture of the R and S optical isomers.

In the context of the present disclosure, N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide refers to the compound having a CAS number of 1202743-51-8 with a molecular weight of 250.27 Da. In the present disclosure, it may be used interchangeably with INT-2. It may also be a mixture of stereoisomers in which the R and S optical isomers are mixed.

In the context of the present disclosure, N- {4- [ (1R) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide hydrochloride refers to the compound having a CAS number of 956901-23-8 with a molecular weight of 286.73Da, and N- {4- [ (1R) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide refers to the compound having a CAS number of 957103-01-4. In this disclosure, N- {4- [ (1R) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide may be used interchangeably with the R isomer of INT-3.

In the context of the present disclosure, 3- (2-propyl-6-trifluoromethylpyridin-3-yl) -acrylic acid refers to a compound having a CAS number of 1005174-17-3 with a molecular weight of 259.22 Da.

In the context of the present disclosure, (R) -N- [1- (3, 5-difluoro-4-methanesulfonylaminophenyl) -ethyl ] -3- (2-propyl-6-trifluoromethylpyridin-3-yl) -acrylamide (PAC-14028) refers to a compound with CAS number 1005168-10-4 with a molecular weight of 491.47 Da.

In one exemplary embodiment of the present disclosure, the R or S optical isomer of INT-3 can be obtained by a method comprising the steps of:

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

adding 10 times the weight of the INT-2 of a polar protic solvent (v/w) to the mixture;

stirring the resulting mixture solution with added polar protic solvent at reflux at 30 ℃ to 70 ℃ for 1 to 4 hours;

cooling the mixture; and

the chiral acid salt of INT-3 was obtained by filtering the resulting solid.

In an exemplary embodiment of the present disclosure, after stirring under reflux, cooling may be performed at 15 to 30 ℃.

In an exemplary embodiment of the present disclosure, the cooling may be performed at the following temperatures: 10 ℃ or more, 15 ℃ or more, 20 ℃ or more, 22 ℃ or more, 24 ℃ or more, 25 ℃ or more, 26 ℃ or more, 28 ℃ or more, 30 ℃ or more or 35 ℃ or more, or 40 ℃ or less, 35 ℃ or less, 30 ℃ or less, 28 ℃ or less, 26 ℃ or less, 25 ℃ or less, 24 ℃ or less, 22 ℃ or less, 20 ℃ or less, 15 ℃ or less, 10 ℃ or less or 5 ℃ or less.

In an exemplary embodiment of the present disclosure, the method may further comprise the step of separating the chiral acid from the obtained chiral acid salt of INT-3. Specifically, the separation may be performed by: the chiral acid salt of INT-3 is added to water (5 times the weight of the chiral acid salt of INT-3) and 2 equivalents of 28 vol% aqueous ammonia solution, a suspension is obtained by stirring for 20 to 50 minutes, the suspension is filtered by removing excess water under reduced pressure and the R or S optical isomer of INT-3 is obtained.

In another aspect, the present disclosure provides a method of chiral resolution of a mixture of stereoisomers, comprising:

(1) a step of mixing a stereoisomer mixture of a compound in which an amine group is bonded to an asymmetric carbon atom with a chiral auxiliary and a salt-forming compound.

In an exemplary embodiment of the present disclosure, the compound may be N- {4- [ (1R/S) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide.

In an exemplary embodiment of the present disclosure, the chiral auxiliary in step (1) may be at least one selected from the group consisting of 2, 3-dibenzoyl tartaric acid, O' -di-p-toluoyl tartaric acid, stereoisomers thereof, and combinations thereof.

In an exemplary embodiment of the present disclosure, the salt-forming compound in step (1) may be at least one selected from the group consisting of mandelic acid, camphorsulfonic acid, stereoisomers thereof, and combinations thereof.

In an exemplary embodiment of the present disclosure, the method may further include, after step (1): (2) a step of adding a solvent to the mixture of step (1).

In one exemplary embodiment of the present disclosure, the solvent may be a polar protic solvent.

In an exemplary embodiment of the present disclosure, the method may further include: (3) a step of stirring the resulting mixture solution under reflux.

In an exemplary embodiment of the present disclosure, the stirring in step (3) may be performed for 30 minutes or more, 1 hour or more, 1.5 hours or more, 2 hours or more, 2.5 hours or more, 3 hours or more, 3.5 minutes or more or 4 hours or more, or 5 hours or less, 4.5 hours or less, 4 hours or less, 3.5 hours or less, 3 hours or less, 2.5 hours or less, 2 hours or less, 1.5 hours or less, 1 hour or less or 30 minutes or less.

In an exemplary embodiment of the present disclosure, the stirring in step (3) may be performed at the following temperature: 20 ℃ or more, 25 ℃ or more, 30 ℃ or more, 35 ℃ or more, 40 ℃ or more, 45 ℃ or more, 50 ℃ or more, 55 ℃ or more or 60 ℃ or more, or 70 ℃ or less, 65 ℃ or less, 60 ℃ or less, 55 ℃ or less, 50 ℃ or less, 45 ℃ or less, 40 ℃ or less, 35 ℃ or less, 30 ℃ or less, 25 ℃ or less or 20 ℃ or less.

In an exemplary embodiment of the present disclosure, the method may further include: (4) a step of cooling the mixture of step (3).

In an exemplary embodiment of the present disclosure, the method may further include: (5) a step of obtaining diastereomeric salts of the compounds by filtering the obtained solid. Specifically, in one exemplary embodiment of the present disclosure, the diastereomeric salt of the compound can be a diastereomeric salt of INT-3.

In an exemplary embodiment of the present disclosure, the method may further include: (6) a step of removing or separating the chiral acid from the resulting diastereomeric salt.

In an exemplary embodiment of the present disclosure, the step (6) may include: 1) a step of adding the diastereomeric salt of INT-3 to a solution of water and aqueous ammonia. Specifically, in one exemplary embodiment of the present disclosure, the amount of water used in step (6) may be 2-fold or more, 3-fold or more, 4-fold or more, 5-fold or more, 6-fold or more or 7-fold or more, or 7-fold or less, 6-fold or less, 5-fold or less, 4-fold or less, 3-fold or less or 2-fold or less based on the weight of the diastereomeric salt of INT-3. Specifically, in one exemplary embodiment of the present disclosure, the aqueous ammonia solution in step (6) may be a 20 vol% or more, 24 vol% or more, 28 vol% or more, 32 vol% or more, 36 vol% or more or 40 vol% or more aqueous ammonia solution, or a 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 aqueous ammonia solution. Specifically, in one exemplary embodiment of the present disclosure, the amount of the aqueous ammonia solution used in step (6) may be 0.5 equivalents or more, 1 equivalent or more, 1.5 equivalents or more, 2 equivalents or more, 2.5 equivalents or more or 3 equivalents or more, or 4 equivalents or less, 3.5 equivalents or less, 3 equivalents or less, 2.5 equivalents or less, 2 equivalents or less, 1.5 equivalents or less, 1 equivalent or less or 0.5 equivalents or less.

In an exemplary embodiment of the present disclosure, step (6) may further include, after step 1): 2) a step of stirring the resulting mixture solution. Specifically, in one exemplary embodiment of the present disclosure, the stirring in step (6) may be 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, or 70 minutes or less, 60 minutes or less, 50 minutes or less, 40 minutes or less, 30 minutes or less, 20 minutes or less or 10 minutes or less.

In an exemplary embodiment of the present disclosure, the step (6) may further include: 3) and (c) filtering the resulting suspension.

In an exemplary embodiment of the present disclosure, the step (6) may further include: 4) a step of obtaining the R or S optical isomer of INT-3 by removing water from the filtered suspension, in particular under reduced pressure.

In another aspect, the invention provides a process for preparing a compound of formula (IIIa) or (IIIb)

Wherein R is₁、R₂、R₃、R₄、R₅、R₆And R₇Each independently selected from H, -NH₂、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Any one of alkynyl and halogen, and

R₁and R₂Different from each other, the methodThe method comprises

Resolving, in particular chirally resolving, said mixture of stereoisomers of a compound of formula (I) according to the methods of the present disclosure, and

converting the resulting stereoisomer to a compound of formula (IIIa) or (IIIb). The transformation procedure is also specifically described in Korean patent application No. 10-2009-700433.

In an exemplary embodiment of the present disclosure, the compound of formula (IIIa) may be (R) -N- [1- (3, 5-difluoro-4-methanesulfonylamino-phenyl) -ethyl ] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide and the compound of formula (I) may be N- {4- [ (1R/S) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide.

In another exemplary embodiment of the present disclosure, the converting step may include the step of coupling N- {4- [ (1R) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide (INT-3) with 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (INT-7).

The R isomer compound resolved by the method according to the present disclosure may be reacted with the substances described in korean patent application No.10-2009-700433, and used as an intermediate for the preparation of novel drugs described in the patent application. Therefore, in another aspect, the present disclosure relates to a method for preparing a novel drug described in korean patent application No.10-2009-700433, which uses an R isomer compound resolved by the method according to the present disclosure, or to a novel drug prepared by the method.

In an exemplary embodiment of the present disclosure, there is provided (R) -N- [1- (3, 5-difluoro-4-methanesulfonylaminophenyl) -ethyl ] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide, obtainable by the process of the present disclosure, having an enantiomeric excess of at least 96%, at least 97%, at least 98%, at least 99%, or 96% to 99%.

In another aspect, the present disclosure provides TRPV1 antagonists comprising as an active ingredient (R) -N- [1- (3, 5-difluoro-4-methanesulfonylaminophenyl) -ethyl ] -3- (2-propyl-6-trifluoromethylpyridin-3-yl) -acrylamide (PAC-14028) prepared according to the methods of the present disclosure. The TRPV1 antagonists may be used in pharmaceutical compositions for the prevention or treatment of the diseases described below.

In yet another aspect, the present disclosure relates to a pharmaceutical composition comprising (R) -N- [1- (3, 5-difluoro-4-methanesulfonylaminophenyl) -ethyl ] -3- (2-propyl-6-trifluoromethylpyridin-3-yl) -acrylamide, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the prevention or treatment of a disease associated with pathological stimulation and/or aberrant expression of vanilloid receptor selected from the group consisting of: pain, arthritic diseases, neuropathies, HIV-associated neuropathies, nerve injury, neurodegeneration, stroke, urinary incontinence, cystitis, gastric/duodenal ulcers, Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD), fecal urgency, gastroesophageal reflux disease (GERD), crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neuropathic/allergic/inflammatory dermatoses, psoriasis, pruritus, prurigo, skin irritation, ocular or mucosal inflammation, auditory hypersensitivity, tinnitus, vestibular hypersensitivity, episodic vertigo, myocardial ischemia, hirsutism, alopecia, rhinitis, and pancreatitis.

In an exemplary embodiment of this aspect of the disclosure, the pain may be or be associated with a disease selected from: osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, fibromyalgia, myofascial pain syndrome, back pain, migraine and other types of headache.

In another aspect, the present disclosure provides a composition comprising: a chiral auxiliary which is one or more selected from the group consisting of 2, 3-dibenzoyl-tartaric acid, O' -di-p-toluoyl-tartaric acid, stereoisomers thereof, and combinations thereof; and a salt former compound that is one or more selected from the group consisting of mandelic acid, camphorsulfonic acid, stereoisomers thereof, and combinations thereof. In one aspect, the composition may be a chiral resolving composition or a chiral resolving agent.

In an exemplary embodiment of the composition according to the invention, the molar equivalent ratio of the chiral auxiliary to 1 molar equivalent of the mixture of stereoisomers to be resolved may be equal to or less than 0.5, alternatively from 0.15 to 0.5, from 0.25 to 0.35 or 0.25.

In an exemplary embodiment of the composition according to the invention, the molar equivalent ratio of the salt-forming compound to 1 molar equivalent of the mixture of stereoisomers to be resolved may be from 0.75 to 1.5.

In an exemplary embodiment of the invention, the molar equivalent ratio of salt compound to 1 molar equivalent of chiral auxiliary in the composition may be from 1.5 to 6, specifically from 3 to 6 (i.e., from 3 to 6 moles of salt compound per mole of chiral auxiliary).

In another aspect, the present disclosure provides a composition comprising: a chiral auxiliary; and a salt-forming compound.

In an exemplary embodiment of the present disclosure, the composition may contain 0.10 to 0.5 equivalent of the chiral auxiliary per 1 equivalent of the stereoisomer mixture requiring chiral resolution.

In an exemplary embodiment of the present disclosure, the composition may contain 0.75 to 1.5 equivalents of salt-forming compound per 1 equivalent of the stereoisomer mixture.

In another aspect, the present disclosure provides a resolution kit comprising a chiral auxiliary and a salt-forming compound.

In another aspect, the present disclosure provides a chiral resolution kit comprising: a chiral auxiliary which is one or more selected from the group consisting of 2, 3-dibenzoyl-tartaric acid, O' -di-p-toluoyl-tartaric acid, stereoisomers thereof, and combinations thereof; and a salt former compound that is one or more selected from the group consisting of mandelic acid, camphorsulfonic acid, stereoisomers thereof, and combinations thereof.

In an exemplary embodiment of the present disclosure, the chiral resolution kit according to the present invention may further comprise written instructions for the use of chiral auxiliary agents and salt-forming compounds, in particular for resolving a mixture of stereoisomers of the compound of formula (I).

In an exemplary embodiment of the invention, the molar equivalent ratio of chiral auxiliary to 1 equivalent of the mixture of stereoisomers to be resolved may be equal to or less than 0.5, from 0.15 to 0.5, from 0.25 to 0.35 or 0.25.

In an exemplary embodiment of the invention, the molar equivalent ratio of salt-forming compound to 1 equivalent of the mixture of stereoisomers to be resolved may be from 0.75 to 1.5.

In an exemplary embodiment of the present disclosure, the kit according to the invention may further comprise written instructions for the use of the chiral auxiliary and the salt-forming compound.

In an exemplary embodiment of the present disclosure, the written instructions may include instructions that the chiral auxiliary is used in an amount of 0.10 to 0.5 equivalents per 1 equivalent of the mixture of stereoisomers requiring chiral resolution.

In an exemplary embodiment of the present disclosure, the written instructions may include instructions that the salt-forming compound is used in an amount of 0.75 to 1.5 equivalents per 1 equivalent of the mixture of stereoisomers requiring chiral resolution.

In one exemplary embodiment of the chiral resolution kit according to the invention, the molar equivalent ratio of salt-forming compound to 1 molar equivalent of chiral auxiliary may be from 1.5 to 6, in particular from 3 to 6 (i.e. from 3 to 6 moles of salt-forming compound per mole of chiral auxiliary).

In an exemplary embodiment of the present disclosure, the written description may include instructions to combine the chiral auxiliary and salt former compound with the mixture of stereoisomers in a polar protic solvent.

In an exemplary embodiment of the present disclosure, the written description may include instructions regarding the methods described in the present disclosure for resolving a mixture of stereoisomers.

In another aspect, the present disclosure provides the use of a composition or kit according to the present disclosure for chiral resolution of a mixture of stereoisomers.

Hereinafter, the present disclosure will be described in detail by the following examples. However, the following examples are for illustrative purposes only, and the scope of the present disclosure is not limited by these examples. In addition, it will be apparent to those skilled in the art that various changes and modifications may be made thereto without departing from the scope of the disclosure.

Comparative test example 1 measurement of optical purity of conventional asymmetric Synthesis method

Asymmetric synthesis was performed according to scheme 2.

[ scheme 2]

Based on N- {2, 6-difluoro-4- [1- (2-methylpropane-2-sulfinylamino) -ethyl]Tetrahydrofuran (THF) (20mL) in an amount 10 times the weight of phenyl } -methanesulfonamide was dissolved. Adding NaBH to the obtained solution₄After (4 equivalents) further dissolution, the reaction was carried out at the temperature described in table 1 for 10 hours. Then, CH was added dropwise₃OH until no hydrogen evolution is observed.

The mixture was concentrated under reduced pressure and then purified by chromatography to give N- {2, 6-difluoro-4- [1- (2-methylpropane-2-sulfinylamino) -ethyl ] -phenyl } -methanesulfonamide. The mixture was stirred at room temperature for 30 minutes while an excess of 4M HCl in dioxane was added dropwise, then concentrated under reduced pressure. The resulting residue was purified by recrystallization from acetone to give (R) -N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide hydrochloride.

The enantiomeric excess (ee%) of the obtained salt was measured in the same manner as in the test example. The results are shown in table 1.

[ Table 1]

Comparative example	Addition of NaBH4Temperature (. degree.C.) during the period	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	94.2

As can be seen from table 1, in order to achieve 96% or more optical activity with the existing method, the temperature should be continuously maintained below-40 ℃ for 10 hours, while the same optical activity can be achieved by stirring and purification at 50 ℃ according to the present disclosure. Thus, it can be seen that the process of the present disclosure is very economical compared to existing processes. If the reaction is scaled up to plant scale, it is easier to maintain the temperature at 50 ℃ for 10 hours than at-40 ℃ for 10 hours. Thus, the reaction scale of the process of the present disclosure can be more easily scaled up than existing processes.

Furthermore, the existing method using 2 to 4 equivalents of sodium borohydride is very dangerous because explosive hydrogen is generated in excess and heat is also generated during the reaction. In contrast, the process of the present disclosure makes it possible to prepare commercially useful stereoisomers having optical activity of 96% or more without involving excessive generation of explosive hydrogen or heat.

In summary, the process of the present disclosure is more economical and safe compared to existing processes.

Comparative test example 2 measurement of optical purity of resolution Using a chiral resolving agent

According to Bioorganic & Medicinal Chemistry 15(18), 6043-6053; preparation described in 2007 prepared N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide (a mixture of R and S stereoisomers). 1 equivalent of the prepared N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide was mixed with 1 equivalent of the chiral auxiliary described in tables 2 and 3. To the resulting mixture was added 10 times (volume) solvent based on the weight of N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide (different solvents as described in the table). The resulting mixture solution was refluxed at 50 ℃ for 3 hours, and then cooled to 25 ℃. The resulting solid was filtered using a buchner funnel to give each of the chiral salts of N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide. The obtained salt is a primary resolved salt.

To the obtained once-resolved N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide salt was added ten times the weight of the solvent, followed by 1 and 2 times the above-mentioned reflux procedure, cooling and then filtration to obtain twice-resolved and three-resolved N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide salt.

To each of the obtained chiral acid salts of N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide was added 5 times the weight of water and 2 equivalents of a 28% by volume aqueous ammonia solution, and the mixture was stirred for 30 minutes. The resulting suspension was filtered using a buchner funnel and excess water was removed under reduced pressure to give N- [4- (1R) -1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide or N- [4- [ (1S) -1-aminoethyl ] -2, 6-difluorophenyl ] -methanesulfonamide (INT-3).

The optical purity (enantiomeric excess) of the INT-3 obtained was analyzed using a Chiral HPLC column (Shiseido Chiral CD-Ph, 4.6 mm. times.250 mm, 5 μm). A mixed solution of 0.5mol/L sodium perchlorate and methanol (75 vol%: 25 vol%) was used as a mobile phase, and the optical purity (enantiomeric excess, ee%) of each chiral acid salt was measured using a Waters e2695alliance hplc system and calculated according to equation 1. And, the yield of the reaction was calculated according to equation 2. The yield of only the three resolved salts with the highest optical activity was calculated.

The results are shown in tables 2 and 3.

< HPLC Condition >

1. Column temperature 35 deg.C

2. Flow rate 0.5 mL/min

3. Detection wavelength of 220nm

4.R_t(min) ═ 20.4 (R-enantiomer%), 18.9 (S-enantiomer%)

[ equation 1]

[ equation 2]

Actual yield: amount of product obtained.

Theoretical yield: maximum amount of product obtainable from a given amount of reactants

[ Table 2]

[ Table 3]

As can be seen from tables 2 and 3, when only dibenzoyltartaric acid or ditoluoyltartaric acid was used, optical isomers of higher purity could be obtained as the number of resolution times increased. In particular, the purity is highest when methanol or ethanol is used. However, when the resolution is performed less than 3 times, the purity is very low compared to a commercially useful purity of at least 96% ee.

Furthermore, when only dibenzoyltartaric acid or ditoluoyl tartaric acid is used, the isomer yield is very low, e.g. below 20%, regardless of the solvent.

Test example 1 measurement of optical purities of different chiral auxiliary Agents and auxiliary salt-Forming Compounds and mixing ratios thereof

According to Bioorganic & Medicinal Chemistry 15(18), 6043-6053; preparation described in 2007 prepared N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide (a mixture of stereoisomers of the R and S isomers). 1 equivalent of the prepared N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide was mixed with the chiral auxiliary and the auxiliary salt-forming compound described in the tables 4 to 8 in the equivalent amounts. To the resulting mixture was added 10 times the weight of the solvent (different solvents as described in tables 4 to 8) based on the weight of the methanesulfonamide compound. The resulting mixture solution was refluxed at 50 ℃ for 3 hours, and then cooled to 25 ℃. The resulting solid was filtered using a buchner funnel to give each INT-3 chiral acid salt.

To each of the obtained chiral acid salts of N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide was added 5 times the weight of water and 2 equivalents of a 28% by volume aqueous ammonia solution, and the mixture was stirred for 30 minutes. The resulting suspension was filtered using a buchner funnel and excess water was removed under reduced pressure to give N- [4- (1R) -1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide or N- [4- (1S) -1-aminoethyl) -2, 6-difluorophenyl ] -methanesulfonamide (INT-3).

The optical purity (enantiomeric excess) of the INT-3 obtained was analyzed using a Chiral HPLC column (Shiseido Chiral CD-Ph, 4.6 mm. times.250 mm, 5 μm). A mixed solution of 0.5mol/L sodium perchlorate and methanol (75 vol%: 25 vol%) was used as a mobile phase, and the optical purity (enantiomeric excess, ee%) of each chiral acid salt was measured using a Waters e2695 Alinace HPLC system.

The results are shown in tables 4 to 8. Table 4 shows the results of such tests, whether the optical purity or the yield of INT-3 is affected by the optical activity of mandelic acid, one of the auxiliary salt-forming compounds. Table 5 shows the results when 2, 3-dibenzoyltartaric acid and mandelic acid were used. Table 6 shows the results when 2, 3-dibenzoyltartaric acid and camphorsulfonic acid were used. Table 7 shows the results when di-p-toluoyltartaric acid and mandelic acid were used. Table 8 shows the results when using ditoluoyltartaric acid and camphorsulfonic acid. Each table shows the results of using different solvents to obtain chiral acid salts.

< HPLC Condition >

1. Column temperature 35 deg.C

2. Flow rate 0.5 mL/min

3. Detection wavelength of 220nm

4.R_t(min) ═ 20.4 (R-enantiomer%), 18.9 (S-enantiomer%)

The optical purity was calculated according to equation 1, and the yield of the reaction was calculated according to equation 2.

Camphorsulfonic acid, mandelic acid, 2, 3-dibenzoyltartaric acid, and O, O' -di-p-toluyltartaric acid used in the experiments were purchased from Sigma Aldrich.

[ Table 4]

[ Table 5]

For mandelic acid, the D and L isomers gave the same results.

[ Table 6]

For camphorsulfonic acid, the R and S isomers gave the same results.

[ Table 7]

For mandelic acid, the D and L isomers gave the same results.

[ Table 8]

For camphorsulfonic acid, the R and S isomers gave the same results.

As can be seen from Table 4, the optical activity of mandelic acid as a soluble salt-forming compound did not affect the optical resolution. In particular, almost the same results were obtained when D or L mandelic acid or mixtures thereof were used. Thus, it can be seen that tartaric acid derivatives such as dibenzoyltartaric acid play an important role in optical resolution.

From tables 5 to 8, it can be seen that when diacyltartaric acid is used for optical resolution, 2 equivalents (molecules) of N- [4- (1-aminoethyl) -phenyl ] -methanesulfonamide and 1 equivalent (molecule) of diacyltartaric acid form salts in polar solvents such as water, methanol, ethanol and isopropanol, as described in scheme 1.

Furthermore, as can be seen from tables 5 to 8, for a given equivalent of mandelic acid and camphorsulfonic acid, when diacyltartaric acid is used in amounts of 0.25 equivalents, 0.35 equivalents, 0.5 equivalents, and 1 equivalent, the optical purity is highest when 0.25 equivalents are used, followed by 0.35 equivalents and 0.5 equivalents. When 1 equivalent of diacyltartaric acid is used, the optical purity is very low.

Thus, it can be seen that 2 equivalents (molecule) of N- [4- (1-aminoethyl) -phenyl ] -methanesulfonamide and 1 equivalent (molecule) of diacyltartaric acid form selectively resolvable salts in polar solvents such as water, methanol, ethanol and isopropanol.

Specifically, referring to tables 5 and 6 in which 2, 3-dibenzoyl-D-tartaric acid and mandelic acid or camphorsulfonic acid were used, when water was used as the solvent, the optical purity was as low as 89% ee or less. When methanol or ethanol is used, when 0.25 equivalents or 0.35 equivalents of tartaric acid is used, the optical purity is 96% ee or more, but the yield is 25% or less. However, the yield was 2-fold or higher compared to when only 2, 3-dibenzoyl-D-tartaric acid was used (see table 2). In particular, when the solvents are methanol and mandelic acid, no resolution occurs when 0.5 equivalent of dibenzoyl-D-tartaric acid is used, but resolution occurs when camphorsulfonic acid is used. When the solvent is isopropanol, when 0.25 equivalents, 0.35 equivalents or 0.5 equivalents of tartaric acid are used, an optical purity of 96% ee or higher can be obtained, and the yield is also 20% or higher. In particular, when 0.25 equivalents or 0.35 equivalents of tartaric acid was used, the yield was 40% or higher.

Based on these results, experiments were conducted in isopropanol in which the equivalent of tartaric acid was fixed while varying the equivalent of mandelic acid or camphorsulfonic acid (examples 2-17 to 2-22 and examples 3-17 to 3-22). Therefore, when 0.5 equivalent or less of tartaric acid is used, when 0.75 to 1.5 equivalents of mandelic acid or camphorsulfonic acid are used, the R isomer having high optical purity of 96% ee or more and high yield can be obtained. In particular, an isomer having a high optical purity of 96% ee or more can be obtained, and the highest yield of 42% is obtained in examples 2 to 17.

Referring to tables 7 and 8 in which O, O' -di-p-toluoyltartaric acid and mandelic acid or camphorsulfonic acid were used, when water was used as the solvent, the optical purity was as low as 80% ee or less. When methanol or ethanol is used, when 0.25 equivalents or 0.35 equivalents of tartaric acid is used, the optical purity is 96% ee or more, but the yield is 25% or less. However, the yield was 2 times or more as compared with when only O, O' -di-p-toluoyltartaric acid was used (see table 3). Further, when camphorsulfonic acid is used, when 0.5 equivalent of di-p-toluoyltartaric acid is used, optical resolution occurs in methanol. When the solvent is isopropanol, when 0.25 equivalents, 0.35 equivalents or 0.5 equivalents of tartaric acid are used, an optical purity of 96% ee or higher can be obtained, and the yield is also 20% or higher. In particular, when 0.25 equivalents or 0.35 equivalents of tartaric acid was used, the yield was 34% or higher.

In examples 4-17 to 4-22 and examples 5-17 to 5-22, experiments were conducted in isopropanol in which the equivalent amount of tartaric acid was fixed while varying the equivalent amount of mandelic acid or camphorsulfonic acid. Therefore, when 0.5 equivalent or less of tartaric acid is used, when 0.75 to 1.5 equivalents of mandelic acid or camphorsulfonic acid are used, the R isomer having high optical purity of 96% ee or more and high yield can be obtained. In particular, isomers having high optical purity of 96% ee or more can be obtained, and the highest yield of 40% is obtained in examples 4 to 17.

In conclusion, when 0.25 to 0.5 equivalents of diacyltartaric acid and 0.75 to 1.5 equivalents of mandelic acid or camphorsulfonic acid are used, the R isomer having a high optical purity of 96% ee or more can be obtained. In particular, when the solvent is isopropanol, a higher yield of the isomer may be obtained. Further, when the solvent is isopropanol, by using 0.25 to 0.35 equivalents of diacyltartaric acid and 0.75 to 1.5 equivalents of mandelic acid or camphorsulfonic acid, an isomer having a high optical purity of 96% ee or more can be obtained in a yield of 30% or more.

It will be apparent to those skilled in the art that when 2, 3-dibenzoyltartaric acid or O, O' -di-p-benzoyltartaric acid is the L isomer, N- {4- [ (1S) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide will be obtained.

Thus, R or S optical isomers of high optical purity can be obtained by the process according to the present disclosure.

[ test example 2] (R) -preparation of N- [1- (3, 5-difluoro-4-methanesulfonylaminophenyl) -ethyl ] -3- (2-propyl-6-trifluoromethylpyridin-3-yl) -acrylamide

According to the method described in Korean patent application No.10-2009-700433, (R) -N- [1- (3, 5-difluoro-4-methanesulfonylaminophenyl) -ethyl ] -3- (2-propyl-6-trifluoromethylpyridin-3-yl) -acrylamide was prepared using N- {4- [ (1R) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide prepared according to the present disclosure.

Specifically, N- {4- [ (1R) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide hydrochloride (62mg, 0.22mmol) was reacted with 3- (2-propyl-6-trifluoromethylpyridin-3-yl) -acrylic acid (56mg, 0.22 mmol). The product was purified by crystallization from ether to give the title compound (81mg, 73%).

¹H NMR(300MHz，DMSO-d₆)：9.50(bs，1H)，8.81(d，1H，J＝7.8Hz)，8.16(d，1H，J＝8.4Hz)，7.80(d，1H，J＝7.8Hz)，7.67(d，1H，J＝15.6Hz)，7.18(d，2H，J＝7.2Hz)，6.76(d，1H，J＝15.6Hz)，5.04(m，1H)，3.05(s，3H)，2.91(m，2H)，1.65(m，2H)，1.41(d，3H，J＝6.9Hz)，0.92(t，3H，J＝7.2Hz).

ESI[M+H]⁺：492

Therefore, the R isomer of the compound having the structure of formula (I), which has been resolved by the method according to the present disclosure, can be used as an intermediate to prepare a variety of novel compounds that can be TRPV1 antagonists using the method or substance described in korean patent application No. 10-2009-700433.

Hereinafter, formulation examples of the composition according to the present disclosure will be described. However, the following examples are for illustrative purposes only, and it is apparent to those of ordinary skill in the art that the scope of the present disclosure is not limited by the examples.

[ formulation example 1] amorphous chiral resolving agent composition

The amorphous solid chiral resolving agent comprises 0.15 to 0.5 equivalents of at least one of 2, 3-dibenzoyltartaric acid and O, O' -di-p-toluyltartaric acid per 1 equivalent of the mixture of stereoisomers; and 0.75 to 1.5 equivalents of at least one of mandelic acid and camphorsulfonic acid.

[ formulation example 2] crystalline chiral resolving agent composition

The crystalline solid chiral resolving agent comprises from 0.15 to 0.5 equivalents of at least one of 2, 3-dibenzoyltartaric acid and O, O' -di-p-toluyltartaric acid per 1 equivalent of the mixture of stereoisomers; and 0.75 to 1.5 equivalents of at least one of mandelic acid and camphorsulfonic acid.

Claims (34)

1. A process for the chiral resolution of a mixture of stereoisomers of a compound of formula (I),

wherein R is₁、R₂、R₃、R₄、R₅、R₆And R₇Each independently selected from H, -NH₂、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Of alkinyl and halogenEither, and R₁And R₂Are different from each other in that,

the process comprises mixing the mixture of stereoisomers of the compound of formula (I) in the presence of a solvent with:

(i) a chiral auxiliary; and

(ii) an auxiliary salifying compound is added to the reaction mixture,

whereby said diastereomeric salt of the chiral auxiliary (I) with the compound of formula (I) is precipitated in enantiomeric excess.

2. The process of claim 1, wherein the chiral auxiliary agent is one or more selected from the group consisting of 2, 3-dibenzoyltartaric acid, O' -di-p-toluyltartaric acid, stereoisomers thereof, and combinations thereof, and the auxiliary salt-forming compound is one or more selected from the group consisting of mandelic acid, camphorsulfonic acid, stereoisomers thereof, and combinations thereof.

3. The method of claim 1, wherein R₂Is hydrogen and when the chiral auxiliary is selected from the group consisting of (+) -2, 3-dibenzoyl-D-tartaric acid, (+) -O, O' -di-p-toluoyl-D-tartaric acid and combinations thereof, the R enantiomer of the compound of formula (I) is obtained in enantiomeric excess.

4. The method of claim 1, wherein R₂Is hydrogen and when the chiral auxiliary is selected from the group consisting of (-) -2, 3-dibenzoyl-L-tartaric acid, (-) -O, O' -di-p-toluoyl-L-tartaric acid and combinations thereof, the S enantiomer of the compound of formula (I) is obtained in enantiomeric excess.

5. The process of claim 1, wherein the auxiliary salt-forming compound is D-mandelic acid, L-mandelic acid, (1R) - (-) -10-camphorsulfonic acid, (1S) - (+) -10-camphorsulfonic acid, or a combination thereof.

6. The method of claim 1, wherein the halogen is one or more selected from the group consisting of F, Cl, Br, and I.

7. The method of claim 6, wherein R₁Selected from methyl, ethyl, propyl, butyl and pentyl, and R₂Is hydrogen.

8. The method of claim 7, wherein R₁Is methyl, R₂、R₃And R₇Is hydrogen, and R₄、R₅And R₆Independently selected from F, Cl, methyl, ethyl and propyl.

9. The process of claim 8 wherein the compound of formula (I) is N- {4- [ (1R/S) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide.

10. The method of claim 1, wherein the solvent is selected from water, C_1-14One or more of alcohols, acetic acid, nitromethane, propionic acid, formic acid, and combinations thereof.

11. The method of claim 10, wherein the solvent is one or more selected from the group consisting of water, methanol, ethanol, and isopropanol.

12. The method of claim 11, wherein the solvent is methanol, isopropanol, or a combination thereof.

13. The method of claim 1, wherein the solvent is added in an amount to achieve complete dissolution of all reactants.

14. The method of claim 13, wherein the solvent is added in an amount of 5-fold to 15-fold (volume/weight) based on the total weight of the mixture of stereoisomers of the compound of formula (I).

15. The method of claim 1, wherein the mixing is performed at 40 ℃ to 70 ℃ or at the boiling point of the solvent or solvent mixture.

16. The process according to any one of claims 1 to 15, wherein the molar equivalent ratio of the chiral auxiliary to 1 molar equivalent of the mixture of stereoisomers is from 0.10 to 0.5.

17. The method of claim 16, wherein the molar equivalent ratio of the chiral auxiliary to 1 molar equivalent of the mixture of stereoisomers is from 0.2 to 0.3.

18. The process according to any one of claims 1 to 15, wherein the molar equivalent ratio of the auxiliary salt-forming compound to 1 molar equivalent of the mixture of stereoisomers is from 0.5 to 1.5.

19. The process of claim 18, wherein the molar equivalent ratio of the auxiliary salt former compound to 1 molar equivalent of the mixture of stereoisomers is from 0.75 to 1.5.

20. The process according to any one of claims 1 to 15, wherein the molar equivalent ratio of the chiral auxiliary and the auxiliary salt former compound together to 1 molar equivalent of the mixture of stereoisomers is from 0.75 to 2.0.

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

22. The stereoisomer of claim 21, wherein the stereoisomer is N- {4- [ (1R) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide or N- {4- [ (1S) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide.

23. A process for the preparation of a compound of formula (IIIa) or (IIIb)

Wherein R is₁、R₂、R₃、R₄、R₅、R₆And R₇Each independently selected from H, -NH₂、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Any one of alkynyl and halogen, and R₁And R₂Different from each other, the method comprises:

resolving the mixture of stereoisomers of compound of formula (I) according to the process of any one of claims 1 to 16, and

converting the resulting stereoisomer to a compound of formula (IIIa) or (IIIb).

24. A process according to claim 23 wherein the compound of formula (IIIa) is (R) -N- [1- (3, 5-difluoro-4-methanesulfonamido-phenyl) -ethyl ] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide and the compound of formula (I) is N- {4- [ (1R/S) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide.

25. A method according to claim 23, wherein said converting the resulting stereoisomer to a compound of formula (IIIa) or (IIIb) comprises coupling N- {4- [ (1R) -1-aminoethyl ] -2, 6-difluorophenyl } methanesulfonamide (INT-3) with 3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylic acid (INT-7).

(R) -N- [1- (3, 5-difluoro-4-methanesulfonylaminophenyl) -ethyl ] -3- (2-propyl-6-trifluoromethyl-pyridin-3-yl) -acrylamide obtained by the process of claim 23 with an enantiomeric excess of 96% to 99%.

27. A composition comprising a chiral auxiliary and an auxiliary salt-forming compound, wherein the chiral auxiliary is one or more selected from the group consisting of 2, 3-dibenzoyl-tartaric acid, O' -di-p-toluoyl-tartaric acid, stereoisomers thereof, and combinations thereof, and the auxiliary salt-forming compound is one or more selected from the group consisting of mandelic acid, camphorsulfonic acid, stereoisomers thereof, and combinations thereof.

28. The composition of claim 27, wherein the composition comprises 0.10 to 0.5 molar equivalents of the chiral auxiliary, based on 1 molar equivalent of the mixture of stereoisomers to be resolved.

29. The composition of claim 27, wherein the composition comprises 0.75 to 1.5 molar equivalents of an auxiliary salt former compound, based on 1 molar equivalent of the mixture of stereoisomers to be resolved.

30. A chiral resolution kit comprising: a chiral auxiliary which is one or more selected from the group consisting of 2, 3-dibenzoyl-tartaric acid, O' -di-p-toluoyl-tartaric acid, stereoisomers thereof, and combinations thereof; and an auxiliary salt-forming compound which is one or more selected from mandelic acid, camphorsulfonic acid, stereoisomers thereof or combinations thereof.

31. The kit according to claim 30, wherein the molar equivalent ratio of the chiral auxiliary to 1 molar equivalent of the mixture of stereoisomers to be resolved is from 0.10 to 0.5.

32. The kit according to claim 30, wherein the molar equivalent ratio of the auxiliary salt-forming compound to 1 molar equivalent of the mixture of stereoisomers to be resolved is from 0.75 to 1.5.

33. The kit of claim 30, wherein the kit further comprises written instructions for using the chiral auxiliary and the auxiliary salt former compound to resolve a mixture of stereoisomers.

34. The kit of claim 30, wherein the kit is used for resolving a mixture of stereoisomers of a compound of formula (I) according to claim 1.