# US 10,479,763 B2 · Chiral resolution method of N-[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives

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- Number: US 10,479,763 B2
- Document ID: US10479763B2
- Status: Granted
- Kind: B2
- Application number: 15/325,349
- Filed: 2016-02-15
- Published: 2017-11-30
- Granted: 2019-11-19
- Earliest claimed: 2015-02-17
- Assignees: Amorepacific Corporation
- Applicants: Amorepacific Corporation
- Inventors: Byoung Young Woo; Ki-Wha Lee; Kwang-Hyun Shin; Miyoung Park; Kyoungmi Jung; Joonho Choi; Gyeyoung Choi; Wonkyung Cho; Young-Ho Park
- Web page: https://patentgrep.com/patent/US10479763B2

## CPC

- C07C 303/42: Separation; Purification; Stabilisation; Use of additives
- C07B 57/00: Separation of optically-active compounds
- C07C 63/06: Benzoic acid
- C07C 303/36: of amides of sulfonic acids
- C07C 303/44: Separation; Purification
- C07C 311/08: having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07D 213/56: Amides
- C07B 2200/07: Optical isomers
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present specification relates to a chiral resolution method of a stereoisomer mixture, comprising a step of mixing a stereoisomer mixture of compounds, in which an amine group is bound to an asymmetric carbon atom, with a chiral auxiliary and salt-forming auxiliary compound, wherein the chiral auxiliary is an O,O′-diacyltartaric acid derivative, more specifically, a 2,3-dibenzoyl-tartaric acid or O,O′-di-p-toluoyl tartaric acid, the salt-forming auxiliary compound is mandelic acid or camphorsulfonic acid, and an optical isomer having a high level of optical purity can be obtained by using the method. Therefore, according to one aspect of the present invention, the method can be useful in pharmaceutical or cosmetic field when preparing an optical isomer having a high optical purity.

## Claims

### Claim 1

A method for chiral resolution of a mixture of stereoisomers of a compound of formula (I),
wherein each of R1, R2, R3, R4, R5, R6 and R7 is independently any one selected from a group consisting of H, —NH2, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group and a halogen, and R1 and R2 are different from each other,
comprising mixing said mixture of stereoisomers of the compound of formula (I) with
(i) a chiral auxiliary; and
(ii) an auxiliary salt-forming compound
in the presence of a solvent, thereby precipitating a diastereomeric salt of said chiral auxiliary (i) with the compound of formula (I) in enantiomeric excess,
wherein the chiral auxiliary is one or more selected from a group consisting of 2,3-dibenzoyltartaric acid, O,O′-di-p-toluoyltartaric acid, a stereoisomer thereof, and a combination thereof, and the auxiliary sal-forming compound is one or more selected from a group consisting of mandelic acid, camphorsulfonic acid, a stereoisomer thereof, and a combination thereof.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the chiral auxiliary is one or more selected from a group consisting of 2,3-dibenzoyltartaric acid, O,O′-di-p-toluoyltartaric acid, a stereoisomer thereof, and a combination thereof and the auxiliary salt-forming compound is one or more selected from a group consisting of mandelic acid, camphorsulfonic acid, a stereoisomer thereof, and a combination thereof.

### Claim 3 (depends on 1)

The method according to claim 1, wherein R2 is hydrogen and an S enantiomer of the compound of formula (I) is obtained in enantiomeric excess when the chiral auxiliary is selected from a group consisting of the (−)-2,3-dibenzoyl-L-tartaric acid, (−)-O,O′-di-p-toluoyl-L-tartaric acid and a combination thereof.

### Claim 4 (depends on 1)

The method according to 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.

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 5)

The method according to claim 5, wherein R1 is selected from a group consisting of methyl, ethyl, propyl, butyl and pentyl and R2 is hydrogen.

### Claim 7 (depends on 6)

The method according to claim 6, wherein R1 is methyl, R2, R3 and R7 are hydrogen, and R4, R5 and R6 are independently selected from a group consisting of F, Cl, methyl, ethyl, and propyl.

### Claim 8 (depends on 7)

The method according to claim 7, wherein the compound of formula (I) is N-{4-[(1R/S)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the solvent is one or more selected from a group consisting of water, a C1-14 alcohol, acetic acid, nitromethane, propionic acid, formic acid and a combination thereof.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the solvent is one or more selected from a group consisting of water, methanol, ethanol and isopropyl alcohol.

### Claim 11 (depends on 10)

The method according to claim 10, wherein the solvent is methanol, isopropyl alcohol or a combination thereof.

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 12)

The method according to claim 12, wherein the solvent is added at an amount of 5-15 times (v/w) of based on the total weight of the mixture of stereoisomers of the compound of formula (I).

### Claim 14 (depends on 1)

The method according to claim 1, wherein the mixing is performed at 40-70° C. or at the boiling point of the solvent or solvent mixture.

### Claim 15 (depends on 1)

The method according to claim 1, wherein the molar equivalent ratio of the chiral auxiliary to 1 molar equivalent of the mixture of stereoisomers is 0.10-0.5.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the molar equivalent ratio of the chiral auxiliary to 1 molar equivalent of the mixture of stereoisomers is 0.2-0.3.

### Claim 17 (depends on 1)

The method according to claim 1, wherein the molar equivalent ratio of the auxiliary salt-forming compound to 1 molar equivalent of the mixture of stereoisomers is 0.5-1.5.

### Claim 18 (depends on 17)

The method according to claim 17, wherein the molar equivalent ratio of the auxiliary salt-forming compound to 1 molar equivalent of the mixture of stereoisomers is 0.75-1.5.

### Claim 19 (depends on 1)

The method according to claim 1, wherein the molar equivalent ratio of the chiral auxiliary and the auxiliary salt-forming compound together to 1 molar equivalent of the mixture of stereoisomers is 0.75-2.0.

### Claim 20 (depends on 1)

A method for preparing a compound of formula (IIIa) or (IIIb)
wherein, each of R1, R2, R3, R4, R5, R6 and R7 is independently any one selected from a group consisting of H, —NH2, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group and a halogen, and R1 and R2 are different from each other, comprising
resolving the mixture of stereoisomers of the compound of formula (I) according to the method of claim 1, and
converting the resulting stereoisomer to the compound of formula (IIIa) or (IIIb).

### Claim 21 (depends on 20)

The method according to claim 20, wherein the compound of formula (IIIa) is (R)—N-[1-(3,5-difluoro-4-methanesulfonamino-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridine-3-yl)-acrylamide and the compound of formula (I) is N-{4-[(1R/S)-1-aminoethyl]-2,6-difluorophenyl}methanesulfonamide.

### Claim 22 (depends on 20)

The method according to claim 20, wherein said converting the resulting stereoisomer to the 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-pyridine-3-yl)-acrylic acid (INT-7).