# US 9,040,572 B2 · Method of preparing benzoimidazole derivatives

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- Number: US 9,040,572 B2
- Document ID: US9040572B2
- Status: Granted
- Kind: B2
- Application number: 13/821,067
- Filed: 2011-09-27
- Published: 2013-09-05
- Granted: 2015-05-26
- Earliest claimed: 2010-09-28
- Assignees: Daewoong Pharmaceutical Co., Ltd.
- Applicants: In Woo Kim; Ji Duck Kim; Hong Chul Yoon; Hee Kyoon Yoon; Byung Goo Lee; Joon Hwan Lee; Young Mook Lim; Soo Jin Choi
- Inventors: In Woo Kim; Ji Duck Kim; Hong Chul Yoon; Hee Kyoon Yoon; Byung Goo Lee; Joon Hwan Lee; Young Mook Lim; Soo Jin Choi
- Web page: https://patentgrep.com/patent/US9040572B2

## CPC

- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07B 37/04: Substitution
- C07D 235/18: with aryl radicals directly attached in position 2
- C07D 401/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

This invention relates to a method of preparing a benzoimidazole derivative at high purity and high yield so as to enable the production of the benzoimidazole derivative compound as an antagonist against a vanilloid reactor-1, and particularly to a method of preparing a benzoimidazole derivative at high purity and high yield, wherein the benzoimidazole derivative is synthesized using a novel intermediate, namely, benzaldehyde, and thereby the preparation process is simple so that it can be applied to production.

## Claims

### Claim 1

A method of preparing a benzimidazole compound, comprising the steps of:
1) reacting a compound represented by Chemical Formula 2 below with a compound represented by Chemical Formula 3 below in the presence of a palladium catalyst to prepare a compound represented by Chemical Formula 4 below;
2) reacting the compound represented by Chemical Formula 4 with an oxidant to prepare an intermediate compound wherein said intermediate compound is selected from the group consisting of:
4-(3-chloropyridin-2-yl)-1-naphthaldehyde,
N-(3-fluoro-4′-formylbiphenyl-4-yl)methane sulfoneamide,
4-(3-(trifluoromethyl)pyridin-2-yl)benzaldehyde,
3-(trifluoromethyl)-2,3′-bipyridine-6′-carbaldehyde, and
3-chloro-2,3′-bipyridine-6′-carbaldehyde; and
3) reacting the intermediate compound with a compound represented by the Chemical Formula 6 below, to yield the benzimidazole compound, wherein step 3) is performed using 1,4-benzoquinone as an additive and 1,4-dioxane or acetonitrile as a solvent,
wherein said benzimidazole compound is selected from the group consisting of: 6-tert-butyl-2-(4-(3-chloropyridin-2-yl)naphthalen-1-yl)-1H-benzo[d]imidazole, N-(4′-(4,6-bis(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3-fluorobiphenyl-4-yl)methanesulfoneamide,
6-bromo-2-(3-(trifluoromethyl)-2,3′-bipyridin-6′-yl)-1H-benzo[d]imidazole, 6-bromo-2-(3-(trifluoromethyl)-2,3′-bipyridin-6′-yl)-1H-imidazo[4,5-b]pyridine, 4-chloro-2-(3-chloro-2,3′-bipyridin-6′-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole, and 2-(3-chloro-2,3′-bipyridin-6′-yl)-4,6-bis(trifluoromethyl)-1H-benzo[d]imidazole,
wherein M is B(OH)2, B(i-Pr)2, Sn(CH3)3, or SnBu3,
X is CH or N,
Y is CR5 or N,
R1 is
R2 and R3 each are hydrogen or R2 and R3 together form a benzene ring,
R4 is Br, tert-butyl, or trifluoromethyl,
R5 is hydrogen, Cl, or trifluoromethyl, and
R6 is hydrogen, Cl, or trifluoromethyl.

### Claim 2

A method of preparing a benzimidazole compound, comprising the steps of:
1) reacting a compound represented by Chemical Formula 7 below with a compound represented by Chemical Formula 3 below in the presence of a palladium catalyst to prepare an intermediate compound, wherein said intermediate compound is selected from the group consisting of:
4-(3-chloropyridin-2-yl)-1-naphthaldehyde,
N-(3-fluoro-4′-formylbiphenyl-4-yl)methane sulfoneamide,
4-(3-(trifluoromethyl)pyridin-2-yl)benzaldehyde,
3-(trifluoromethyl)-2,3′-bipyridine-6′-carbaldehyde, and
3-chloro-2,3′-bipyridine-6′-carbaldehyde; and
2) reacting the intermediate compound with a compound represented by Chemical Formula 6 below, to yield the benzimidazole compound, wherein the step 3) is performed using 1,4-benzoquinone as an additive and 1,4-dioxane or acetonitrile as a solvent,
wherein said benzimidazole compound is selected from the group consisting of:
6-tert-butyl-2-(4-(3-chloropyridin-2-yl)naphthalen-1-yl)-1H-benzo[d]imidazole,
N-(4′-(4,6-bis(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3-fluorobiphenyl-4-yl)methanesulfoneamide,
4-bromo-6-(trifluoromethyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)phenyl)-1H-benzo[d]imidazole,
6-bromo-2-(4-(3-(trifluoromethyl)pyridin-2-yl)phenyl)-1H-imidazo[4,5-b]pyridine,
6-(trifluoromethyl)-2-(3-(trifluoromethyl)-2,3′-bipyridin-6′-yl)-1H-benzo[d]imidazole,
6-bromo-2-(3-(trifluoromethyl)-2,3′-bipyridin-6′-yl)-1H-benzo[d]imidazole,
6-bromo-2-(3-(trifluoromethyl)-2,3′-bipyridin-6′-yl)-1H-imidazo[4,5-b]pyridine,
4-(2-(3-(trifluoromethyl)-2,3′-bipyridin-6′-yl)-3H-benzo[d]imidazol-5-yl)morpholine,
4-chloro-2-(3-chloro-2,3′-bipyridin-6′-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole, and
2-(3-chloro-2,3′-bipyridin-6′-yl)-4,6-bis(trifluoromethyl)-1H-benzo[d]imidazole;
wherein M is B(OH)2, B(i-Pr)2, Sn(CH3)3, or SnBu3,
X is CH or N,
Y is CR5 or N,
R1 is
R2 and R3 each are hydrogen or R2 and R3 together form a benzene ring,
R4 is Br, tert-butyl, trifluoromethyl, or morpholino,
R5 is hydrogen, Cl, Br, or trifluoromethyl, and
R6 is hydrogen, Cl, or trifluoromethyl.

### Claim 3 (depends on 1, 2)

The method of claim 1 or 2, wherein said palladium catalyst is any one selected from the group consisting of Pd(PPh3)4, Pd2(dba)3, PdCl2(PPh3)2 and Pd(PtBu3)2.

### Claim 4 (depends on 1, 2)

The method of claim 1 or 2, wherein the step 1) of claim 1 or the step 1) of claim 2 is further performed in the presence of a base.

### Claim 5 (depends on 4)

The method of claim 4, wherein the base is an inorganic base or an organic base.

### Claim 6 (depends on 5)

The method of claim 5, wherein the inorganic base is any one selected from the group consisting of calcium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, potassium tert-butoxide (t-BuOK) and lithium hydroxide.

### Claim 7 (depends on 5)

The method of claim 5, wherein the organic base is any one selected from the group consisting of triethylamine, tert-butylamine, and diisopropylethylamine.

### Claim 8 (depends on 1, 2)

The method of claim 1 or 2, wherein the step 1) of claim 1 or the step 1) of claim 2 is performed using any one solvent selected from the group consisting of ethanol, toluene, 1,2-dimethoxyehtane, a mixture of water and ethanol, a mixture of water and toluene, or a mixture of water and 1,2-dimethoxyethane.

### Claim 9 (depends on 8)

The method of claim 8, wherein the mixture of water and ethanol, the mixture of water and toluene, and the mixture of water and 1,2-dimethoxyethane, a ratio of water and ethanol, water and toluene, and water and 1,2-dimethoxyethane is 100:1˜1:100.

### Claim 10 (depends on 1, 2)

The method of claim 1 or claim 2, wherein the step 1) of claim 1 or the step 1) of claim 2 is performed at 60° C.˜150° C.

### Claim 11 (depends on 1)

The method of claim 1, wherein the oxidant is selenium dioxide or ceric ammonium nitrate.

### Claim 12 (depends on 1)

The method of claim 1, wherein the step 2) is performed using any one solvent selected from the group consisting of 1,4-dioxane, dimethylformamide, tetrahydrofuran, methanol and acetonitrile.

### Claim 13 (depends on 1)

The method of claim 1, wherein the step 2) is further performed in the presence of an acid.

### Claim 14 (depends on 13)

The method of claim 13, wherein the acid is any one selected from the group consisting of hydrochloric acid, nitric acid, sufuric acid, phosphoric acid, acetic acid, p-toluene sulfonic acid (p-TSA), and camphorsulfonic acid (CSA).

### Claim 15 (depends on 13)

The method of claim 13, wherein the acid is added in an amount of 0.01˜1.0 equivalents.

### Claim 16 (depends on 1)

The method of claim 1, wherein the step 2) is performed at 60° C.˜150° C.

### Claim 17 (depends on 1, 2)

The method of claim 1 or 2, wherein the step 3) of claim 1 or the step 2) of claim 2 is performed at 60° C.˜150° C.

### Claim 18

Any one compound selected from the group consisting of:
4-(3-chloropyridin-2-yl)-1-naphthaldehyde,
N-(3-fluoro-4′-formylbiphenyl-4-yl)methane sulfoneamide,
3-(trifluoromethyl)-2,3′-bipyridine-6′-carbaldehyde, and
3-chloro-2,3′-bipyridine-6′-carbaldehyde.