# US 12,180,139 B2 · Method for preparing aminoalkanoic acid derivative containing biphenyl group

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- Number: US 12,180,139 B2
- Document ID: US12180139B2
- Status: Granted
- Kind: B2
- Application number: 17/948,165
- Filed: 2022-09-19
- Published: 2023-02-23
- Granted: 2024-12-31
- Earliest claimed: 2019-06-25
- Assignees: Amtixbio Co., Ltd.
- Applicants: Amtixbio Co., Ltd.
- Inventors: Ki Duk Park; Jong Hyun Park; Hyeon Ji Kim; Ye Rim Lee; Siwon Kim; Ji Won Choi; Seul Ki Yeon; Jong-Seung Lee; Yong-Sun Bahn; Eunji Cheong; Kyung-Tae Lee; Joohyeon Hong
- Web page: https://patentgrep.com/patent/US12180139B2

## CPC

- C07C 231/02: from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
- C07C 237/20: the carbon skeleton containing six-membered aromatic rings
- A61P 31/10: Antimycotics
- A61K 31/165: having aromatic rings, e.g. colchicine, atenolol, progabide
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present invention relates to a derivative compound in which a biphenyl group is introduced into an aminoalkanoic acid, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compound of the present invention exhibits excellent antifungal and fungicidal effects. Furthermore, the compound of the present invention exhibits a synergistic effect when used in combination with a conventional antifungal agent. Furthermore, the compound of the present invention provides broad-spectrum antifungal activity against a wide range of fungal pathogens. Therefore, the compound of the present invention may be widely used in fields requiring treatment with antifungal or fungicidal agents against human pathogenic fungi and animal pathogenic fungi, and phytopathogenic fungi.

## Claims

### Claim 1

A method for preparing a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
1) 2-amino-N-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)butanamide;
2) 2-amino-N-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)pentanamide;
3) 2-amino-N-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)hexanamide;
4) 2-amino-N-(4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)pentanamide;
5) N-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)-2-(methylamino)butanamide;
6) N-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)-2-(methylamino)pentanamide;
7) N-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)-2-(methylamino)hexanamide;
8) N-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)-2-(dimethylamino)pentanamide;
9) 2-amino-N-((3′,4′-dichloro-[1,1′-biphenyl]-4-yl)methyl)pentanamide;
10) 2-amino-N-((3′,4′-dichloro-[1,1′-biphenyl]-4-yl)methyl)hexanamide;
11) 2-amino-N-((4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methyl)pentanamide;
12) 2-amino-N-((4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methyl)hexanamide;
13) 2-amino-N-((4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)methyl)pentanamide;
14) 2-amino-N-((4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)methyl)hexanamide;
15) N-((3′,4′-dichloro-[1,1′-biphenyl]-4-yl)methyl)-2-(methylamino)pentanamide;
16) 2-(methylamino)-N-((4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methyl)pentanamide;
17) N-((3′,4′-dichloro-[1,1′-biphenyl]-4-yl)methyl)-2-(dimethylamino)pentanamide;
18) 2-amino-N-(2-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)ethyl)butanamide;
19) 2-amino-N-(2-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)ethyl)pentanamide;
20) 2-amino-N-(2-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)ethyl)hexanamide;
21) 2-amino-N-(2-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethyl)butanamide;
22) 2-amino-N-(2-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethyl)pentanamide;
23) 2-amino-N-(2-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethyl)hexanamide;
24) 2-amino-N-(2-(4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ethyl)butanamide;
25) 2-amino-N-(2-(4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ethyl)pentanamide;
26) 2-amino-N-(2-(4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ethyl)hexanamide;
27) 2-amino-N-(2-(3′,4′-difluoro-[1,1′-biphenyl]-4-yl)ethyl)pentanamide;
28) N-(2-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)ethyl)-2-(methylamino)butanamide;
29) N-(2-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)ethyl)-2-(methylamino)pentanamide;
30) N-(2-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)ethyl)-2-(methylamino)hexanamide;
31) 2-(methylamino)-N-(2-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethyl)butanamide;
32) 2-(methylamino)-N-(2-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethyl)pentanamide;
33) 2-(methylamino)-N-(2-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethyl)hexanamide;
34) 2-(methylamino)-N-(2-(4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ethyl)butanamide;
35) 2-(methylamino)-N-(2-(4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ethyl)pentanamide;
36) 2-(methylamino)-N-(2-(4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ethyl)hexanamide; and
37) N-(2-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)ethyl)-2-(dimethylamino)pentanamide,
the method comprising:
a first step of forming a peptide bond by reacting an aminoalkanoic acid derivative compound protected by a butoxycarbonyl (Boc) protecting group, which is represented by the following Formula 2, with a biphenyl derivative compound containing a primary amine group, which is represented by the following Formula 3; and
a second step of removing the Boc protecting group by reacting the compound obtained in the first step with an acid:
in the formulae,
n is 0, 1, 2, 3, 4 or 5,
R2 and R3 are each independently the same as or different from each other, and are each independently selected from hydrogen, a C1-7 alkyl, hydroxyl, a halogen, a halogenated C1-7 alkyl, a C1-7 alkyloxy and a halogenated C1-7 alkyloxy, and
X is m substituents (m is an integer from 1 to 5) which are the same as or different from each other, selected from the group consisting of a halogen group, a halogenated C1-7 alkyl group and a halogenated C1-7 alkoxy group.

### Claim 2 (depends on 1)

The method of claim 1, wherein the aminoalkanoic acid derivative compound protected by the Boc protecting group, which is represented by Formula 2 is prepared by reacting an amino acid derivative represented by the following Formula 4 with di-tert-butyl dicarbonate (Boc anhydride):
in the formula,
R1′, R2 and R3 are each independently the same as or different from each other, and are each independently selected from hydrogen, a C1-7 alkyl, hydroxyl, a halogen, a halogenated C1-7 alkyl, a C1-7 alkyloxy and a halogenated C1-7 alkyloxy.

### Claim 3 (depends on 2)

The method of claim 2, wherein when R2 of the finally prepared compound is an alkyl, a step of alkylating the compound by reacting the compound with a haloalkane in the presence of a base after the above reaction is further performed.

### Claim 4 (depends on 1)

The method of claim 1, wherein a biphenyl derivative compound comprising a primary amine group, which is represented by Formula 3 is prepared by reacting a C0-2 alkylamine derivative in which a halophenyl group at one end is substituted, which is represented by the following Formula 5, with di-tert-butyl dicarbonate to introduce a Boc protecting group into an amine group, then reacting the resulting alkylamine derivative with a phenylboronic acid derivative represented by the following Formula 6, and then reacting the reactants with an acid to remove the Boc protecting group:
in the formulae,
X′ is a halogen, and
X is m substituents (m is an integer from 1 to 5) which are the same as or different from each other, selected from the group consisting of a halogen group, a halogenated C1-7 alkyl group and a halogenated C1-7 alkoxy group.

### Claim 5 (depends on 4)

The method of claim 4, wherein the reaction with the phenylboronic acid derivative is achieved by a cross-coupling reaction using a metal catalyst in the presence of a base.

### Claim 6 (depends on 1)

The method of claim 1, wherein the first step is achieved by an anhydride coupling reaction performed in an organic solvent in the presence of N-methylmorpholine (NMM) and isobutyl chloroformate (IBCF).

### Claim 7 (depends on 1)

The method of claim 1, further comprising a third step of forming a secondary amine by alkylating amine after the second step.