WO2011019781A1

WO2011019781A1 - Process for preparing 2-arylamino or heteroarylamino substituted benzimidazole compounds

Info

Publication number: WO2011019781A1
Application number: PCT/US2010/045110
Authority: WO
Inventors: John J. Shay, Jr.; Sithamalli V. Chandramouli; Xiaojie Li; Matthew R. Powers; Timothy A. Ayers; Andrea Hillegass
Original assignee: Sanofi Aventis US LLC
Current assignee: Sanofi Aventis US LLC
Priority date: 2009-08-11
Filing date: 2010-08-11
Publication date: 2011-02-17
Anticipated expiration: 2012-02-11
Also published as: AR077823A1; TW201111350A

Abstract

The present invention is related to a process for preparing 2-arylamino or heteroarylamino substituted benzimidazole compounds.

Description

PROCESS FOR PREPARING 2-ARYLAMINO OR

HETEROARYLAMINO SUBSTITUTED BENZIMIDAZOLE

COMPOUNDS Field of the Invention

The present invention is related to a process for preparing 2-arylamino or heteroarylamino substituted benzimidazole compounds. Background of the Invention

United States Patent No. 7,049,333 (hereinafter the '333 patent) to Lang et. al. discloses certain 2-thienylamino-benzimidazole compounds, particularly 3-chloro- 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine and its hydrochloride salt, possess potent inhibitory properties on the sodium/proton exchanger of subtype 3 ("NHE-3"), which makes the compounds useful for treating respiratory disorders, disorders of the central nervous system, etc. The '333 patent discloses the preparation of 3-chloro-3N-(2-benzimidazolyl)-4-methyl-3- thienylamine hydrochloride, wherein 3N-(2-benzimidazolyl)-4-methyl-3- thienylamine is an intermediate, see Scheme I. The preparation of 3N-(2- benzimidazolyl)-4-methyl-3-thienylamine involves three steps of reactions starting from 4-methyl-3-thienylamine. Difficulties have also been report regarding direct coupling of heteroarylamine, specifically pyridylamine, with 2- methylsulfonylbenzimidazole (See P. Lan et al., Tetrahedron Letters 49 (2008) 1910-1914). Thus, there is a need for a simpler process for preparing 3N-(2- benzimidazolyl)-4-methyl-3-thienylamine.

Scheme I

Summary of the Invention

The present invention is also related to a process for preparing a compound of formula (I)

(I)

wherein:

Ri, R₂. R₃, and R₄ are each independently H, halogen, hydroxyl, d-Cβ alkyl optionally substituted with up to three fluorine, CVCβ alkoxy optionally substituted h up to three fluorine, Ci-Cβ alkoxycarbonyl, C₁-C4 alkoxycarbonylamido, amino or carboxy; and

Ar is phenyl, naphthyl, 3-pyridyl, 4-pyridyl or thienyl, wherein the phenyl and naphthyl are independently optionally substituted by halogen, C_rC₆-alkyl optionally substituted with up to three fluorine, or Ci-Cβ alkoxy optionally substituted up to three fluorine, and wherein the 3-pyridyl, 4-pyridyl and thienyl are independently optionally substituted by C_rC₆-alkyl optionally substituted with up to three fluorine, or Ci-C₆ alkoxy optionally substituted up to three fluorine;

or an acid addition salt thereof;

comprising reacting a compound of formula (II)

(H)

wherein R₁, R₂, R₃ and R₄ are as defined above, with a compound of formula (III)

Ar-NH₂

(III)

or an acid addition salt thereof, wherein Ar is as defined above, optionally in the presence of a suitable base.

Detailed Description of the Invention

As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings.

"Acid addition salt" includes hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulfamates, malonates, salicylates, propionates, methylene-bis-β- hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and laurylsulfonate salts, and the like, particularly hydrochloride. "Ci-Cβ-alkyl" means straight or branched aliphatic hydrocarbon having 1 to 6 carbon atoms.

"Ci-C₆ alkoxy" means -O- d-Ce-alkyl. "C₁-C₆ alkoxycarbonyl" means -C(=O)-O- C_rC₆-alkyl.

"C₁-C₆ alkoxycarbonylamino" means -NH-C(=O)-O- Ci-C₆-alkyl.

"Halogen" means fluoro, chloro, bromo, or iodo. Particular halogen is fluoro or chloro.

"Substituted" means substituted one or more times by same or different substituent groups, particularly substituted one, two or three times by same or different substituent groups; more particularly substituted once by a substituent group.

"Suitable base" includes, for example, potassium dihydrogen phosphate

(KH₂PO₄), potassium carbonate (K₂CO₃), potassium bicarbonate (KHCO₃), sodium carbonate (Na₂CC>₃), sodium bicarbonate (NaHCOa), and 1 ,8- diazabicyclo (5.4.0)undec-7-ene, particularly potassium dihydrogen phosphate.

"Suitable solvent" includes, for example, an alcohol solvent, 2- methyltetrahydrofuran, dimethoxyethane, dimethylformamide (DMF), dioxane, N- methylpyrrolidone (NMP), toluene, dioxolane, dimethyl sulfoxide (DMSO), or 2- ethoxyethylether, or a mixture thereof, particularly an alcohol solvent, more particularly 2-propanol, 1-butanol, sec-butanol, 1-pentanol, or t-amyl alcohol. One particular embodiment of the invention is a process for preparing the compound of formula (I), comprising reacting a compound of formula (II) with a compound of formula (III) or an acid addition salt thereof, in the present of a suitable base.

Another particular embodiment of the invention is a process for preparing the compound of formula (I)₁ wherein R-i, R_∑, R₃, and R₄ are H.

Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein Ar is phenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-ditrifluoromethyl-phenyl, 3-pyridyl, 4-pyridyl or 4-methyl- thiophenyl.

Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein R₃, R₄, R₅ and Re are H, and Ar is 4-methyl- thiophenyl.

Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein the suitable base is potassium dihydrogen phosphate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium bicarbonate, or 1 ,8-diazabicyclo (5.4.0)undec-7-ene.

Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein the suitable base is potassium dihydrogen phosphate.

Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein the reaction is carried out in the presence of a suitable solvent. Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein the reaction is carried out in the presence of an alcohol solvent, 2-methyltetrahydrofuran, dimethoxyethane, dimethylformamide, dioxane, N-methylpyrrolidone, toluene, dioxolane, dimethyl sulfoxide, or 2- ethoxyethylether, or a mixture thereof.

Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein the reaction is carried out in the presence of 2- propanol, 1-butanol, 1-pentanol, sec-butanol, T-amyl alcohol, 2-methyl tetrahydrofuran, dioxane, toluene or a mixture thereof.

Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein the reaction is carried out in the presence of 2- propanol, 1-butanol, 1-pentanol, sec-butanol, T-amyl alcohol, or a mixture thereof.

Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein the reaction is carried out at a temperature about 70⁰C to about 120⁰C. Another particular embodiment of the invention is a process for preparing (1 H- Benzoimidazol-2-yl)-(4-methyl-thiophen-3-yl)-amine hydrochloride, comprising reacting 2-chloro-benzimidazole with 3-amino-4-methylthiophene hydrochloride in the presence of potassium dihydrogen phosphate. Another particular embodiment of the invention is a process for preparing (1 H- Benzoimidazol-2-yl)-(4-methyl-thiophen-3-yl)-amine hydrochloride, comprising reacting 2-chloro-benzimidazole with 3-amino-4-methylthiophene hydrochloride in the presence of potassium dihydrogen phosphate, and 1-butanol. Another particular embodiment of the invention is a process for preparing (1 H- Benzoimidazol-2-yl)-(4-methyl-thiophen-3-yl)-amine hydrochloride, comprising reacting 2-chloro-benzimidazole with 3-amino-4-methylthiophene hydrochloride in the presence of potassium dihydrogen phosphate, and 1-butanol, and at a temperature at about 9O⁰C to about 98⁰C. The process of the present invention provides a simpler process for the direct coupling of certain arylamines and heteroarylamines with 2-chlorobenzimidazole compounds. Particularly, it provides a more cost effective method for preparing 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine. Specifically, the direct coupling of 4-methyl-3-thienylamine and 2-chlorobenzimidazole can be achieved in high yield using a suitable base, such as K₂HPO₄. Furthermore, this process is more cost effective as the materials are less expensive and the waste streams are lower and less toxic.

Examples

The present invention may be better understood by reference to the following non-limiting Examples, which are exemplary of the invention. They should in no way be construed, however, as limiting the broad scope of the invention. Example 1

(1H-Benzoimidazol-2-yl)-(4-methyl-thiophen-3-yl)-amine hydrochloride

A reactor is charged with 0.9 kg (6.01 mol) of 3-amino-4-methylthiophene HCI salt followed by 0.882 kg (5.78 mol) of 2-chlorobenzimidazole, 0.82 kg (6.03 mol) potassium dihydrogen phosphate, and 3 kg (3.7 L) of 1-butanol. The suspension is warmed to 90 °C over an hour and held between 90-98⁰C for 5 h. 3 kg (3.7 L) of 1-butanol is then added. The temperature is adjusted to 50°C. The solids are filtered and washed with 1.5 kg (1.86 L) of 1-butanol warmed to 38°C. The filtrates are combined in a clean reactor and then are distilled under reduced pressure at 100 mbar and at a temperature of 68-71⁰C until 4.83 kg (5.75 L) of distillate is removed. A total of 6.55 kg (7.43 L) of n-butyl acetate is added. The temperature is adjusted to 25°C and held for 30 min. The solids are filtered and washed with a solution of 0.62 kg (0.7 L) of n-butyl acetate and 0.19 kg (0.23 L) of 1-butanol. The filter cake is subsequently washed with 0.79 kg (0.9 L) of n- butyl acetate. After drying in the vacuum oven (45⁰C, 12 mbar) overnight, a total of 1.19 kg (77%) of (1H-Benzoimidazol-2-yl)-(4-methyl-thiophen-3-yl)-amine hydrochloride as a solid is obtained. ¹H NMR (d₆-DMSO) δ 12.93 (bs, 2H), 11.41 (bs, 1 H), 7.72 (d, 1 H), 7.49 (m, 2H), 7.38 (m, 1 H), 7.27 (m, 2H), 2.19 (d, 3H); ¹³C NMR (de-DMSO) δ 149.4, 134.0, 133.8, 130.4, 123.9, 123.1, 120.3, 112.5, 14.0; mp 239-245 ⁰C.

Example 2

(1 H-Benzoimidazol-2-yl)-pyridin-3-yl-amine

A mixture of 3-aminopyridine (1.88 g, 20 mmol), potassium dihydrogenphosphate ^■ (2.72 g, 20 mmol) and 2-chlorobenzimidazole (3.05 g, 20 mmol) in n-BuOH (20 mL) is heated at 80⁰C for 16 h. The reaction is cooled to room temperature and the solid is collected by filtration. The solid is washed with /7-BuOH and then slurried in methanol. The resulting mixture is filtered. The filtrate is concentrated to give 3.7 g (88%) of (1 H-benzoimidazol-2-yl)-pyridin-3-yl-amine. ¹H NMR (d₆- DMSO) δ 9.10 (S₁ 1H), 9.00 (s, 1 H), 9.17 (s, 2H), 7.95 (m, 2H), 7.70 (m, 2H)₁ 7.30 (m, 2H), 7.10 (m, 2H).

Example 3

(1 H-Benzoimidazol-2-yl)-pyridin-4-yl-amine

A mixture of 4-aminopyιϊdine (1.88 g, 20 mmol), potassium dihydrogenphosphate (2.72 g, 20 mmol) and 2-chlorobenzimidazole (3.05g, 20 mmol) in n-BuOH (20 mL) is heated at 110⁰C. A solid is formed during the reaction. After 2.5 days, the reaction is cooled to room temperature and the solid is collected by filtration. The solid is washed with n-BuOH and then slurried in methanol. The resulting mixture is filtered. The filtrate is concentrated to afford 3.4 g (81%) of (1 H- benzoimidazol-2-yl)-pyridin-4-yl-amine. ¹H NMR (d₆-DMSO) δ 9.20 (s, 2H), 8.98 (m, 2H), 7.62 (m, 2H), 7.24 (m, 2H), 7.05 (m, 2H).

Example 4

(1 H-Benzoimidazol-2-yl)-(4-chloro-phenyl)-amine

A mixture of 4-chloroaniline (2.55 g, 20 mmol), potassium dihydrogenphosphate (2.72 g, 20 mmol) and 2-chlorobenzimidazole (3.05 g, 20 mmol) in n-BuOH (40 mL) is heated at 80⁰C. A solid is formed during the reaction. After16 h, the reaction is cooled to room temperature and the solid is collected by filtration. The solid is washed with n-BuOH and then slurried in methanol. The resulting mixture is filtered. The filtrate is concentrated to give 3.8g (79%) of (1H- benzoimidazol-2-yl)-(4-chloro-phenyl)-amine. ¹H NMR (d₆-DMSO) δ 7.55 (s, 4H), 7.45 (m, 2H), 7.27 (m, 2H).

Example 5

(1 H-Benzoimidazol-2-yl)-phenyl-amine

A mixture of aniline (1.86 g, 20 mmol), potassium dihydrogenphosphate (2.72 g, 20 mmol) and 2-chlorobenzimidazole (3.05 g, 20 mmol) in n-BuOH (25 ml_) is heated at 80⁰C. A solid is formed during the reaction. After16 h, the reaction mixture is filtered with washing of the solid with n-BuOH. To the filtrate is added heptane (40 mL) slowly at 65⁰C. The mixture is cooled to room temperature. After 15 h, the solid is collected by filtration and washed with a mixture of heptane/BuOH (2:1). After drying, 3 g (72%) of (1 H-benzoimidazol-2-yl)-phenyl- amine is obtained. ¹H NMR (d₆-DMSO) δ 10.40 (br s, 1 H), 7.64 (m, 2H), 7.30 (m, 4H), 7.00 (m, 3H).

Example 6

(1 H-Benzoimidazol-2-yl)-(4-methoxy-phenyl)-amine

A mixture of 4-methoxyaniline (2.46 g, 20 mmol), potassium

dihydrogenphosphate (2.72 g, 20 mmol) and 2-chlorobenzimidazole (3.05 g, 20 mmol) in n-BuOH (22 mL) is heated at 80⁰C. After 16 h, the reaction is cooled to room temperature and then filtered. The filtrate is concentrated to provide a solid. The solid is collected and washed with minimal n-BuOH. After drying, 3.85g (81%) of (1H-benzoimidazol-2-yl)-(4-methoxy-phenyl)-amine is obtained. ¹H NMR (de-DMSO) δ 11.25 (br s, 1 H), 7.40 (m, 4H), 7.20 (m, 2H), 7.05 (m, 2H)₁ 3.80 (s, 3H). Example 7

(1 H-Benzoimidazol-2-yl)-(3,5-bis-trifluoromethyl-phenyl)-amine

A mixture of 3,5-bistrifluoromethylaniline (1.1 g, 5 mmol), potassium

dihydrogenphosphate (680 mg, 5 mmol) and 2-chlorobenzimidazole (750 mg, 5 mmol) in n-BuOH (22 ml.) is heated at 9O⁰C. After 26 h, the mixture is cooled to room temperature and then filtered. The filtrate is heated to 65⁰C and heptane (20 ml.) is slowly added to give a solid. The mixture is cooled to room temperature. After 2 h, the solid is collected and washed with a mixture of heptane and n-BuOH to give 1.1g (66%) of (1H-benzoimidazol-2-yl)-(3,5-bis- trifluoromethyl-phenyl)-amine. ¹H NMR (d₆-DMSO) .512.20 (br s, 1 H), 8.22 (s, 2H), 7.95 (s, 1H), 7.50 (m, 2H), 7.30 (s, 2H).

Claims

We claim:

1. A process for preparing a compound of formula (I)

(I) wherein:

Ri, R₂, R₃, and R₄ are each independently H, halogen, hydroxyl, CrCβ alkyl optionally substituted with up to three fluorine, CrC₆ alkoxy optionally substituted h up to three fluorine, Ci-C₆ alkoxycarbonyl, CrC₄

alkoxycarbonylamido, amino or carboxy; and

Ar is phenyl, naphthyl, 3-pyridyl, 4-pyridyl or thienyl, wherein the phenyl and naphthyl are independently optionally substituted by halogen, CrCe-alkyl optionally substituted with up to three fluorine, or C_I-CΘ alkoxy optionally substituted up to three fluorine, and wherein the 3-pyridyl, 4-pyridyl and thienyl are independently optionally substituted by Ci-C₆-alkyl optionally substituted with up to three fluorine, or C₁-C₆ alkoxy optionally substituted up to three fluorine;

or an acid addition salt thereof;

comprising reacting a compound of formula (II)

(II)

wherein R₁, R₂, R₃ and R₄ are as defined above, with a compound of formula (III) Ar-NH₂

(III)

2. The process according to claim 1 , comprising reacting the compound of formula (II) with the compound of formula (III) or an acid addition salt thereof, in the present of a suitable base.

3. The process according to claim 1 , wherein R₁, R₂, R₃, and R₄ are H.

4. The process according to claim 1 , wherein Ar is phenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-ditrifluoromethyl-phenyl, 3-pyridyl, 4-pyridyl or

4-methyl-thiophenyl.

5. The process according to claim 1 , wherein R₃, R₄, R₅ and Re are H, and Ar is 4-methyl-thiophenyl.

6. The process according to claim 1 , wherein the suitable base is potassium dihydrogen phosphate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium bicarbonate, or 1 ,8-diazabicyclo (5.4.0)undec-7-ene.

7. The process according to claim 1 , wherein the suitable base is potassium dihydrogen phosphate.

8. The process according to claim 1 , wherein the reaction is carried out in the presence of a suitable solvent.

9. The process according to claim 8, wherein the suitable solvent is an alcohol solvent, 2-methyltetrahydrofuran, dimethoxyethane, dimethylformamide, dioxane, N-methylpyrrolidone, toluene, dioxolane, dimethyl sulfoxide, or 2- ethoxyethylether, or a mixture thereof.

10. The process according to claim 8, wherein the suitable solvent is - propanol, 1-butanol, 1-pentanol, sec-butanol, T-amyl alcohol, 2-methyl tetrahydrofuran, dioxane, toluene or a mixture thereof.

11. The process according to claim 8, wherein the suitable solvent is 2- propanol, 1-butanol, 1-pentanol, sec-butanol, T-amyl alcohol, or a mixture thereof.

12. The process according to claim 1 , wherein the reaction is carried out at a temperature about 70⁰C to about 120⁰C.

13. The process according to claim 1 , wherein for preparing (1 H- Benzoimidazol-2-yl)-(4-methyl-thiophen-3-yl)-amine hydrochloride, comprising reacting 2-chloro-benzimidazole with 3-amino-4-methylthiophene hydrochloride in the presence of potassium dihydrogen phosphate.

14. The process according to claim 13, wherein the reaction is carried out in the presence of 1-butanol.

15. The process according to claim 1 , wherein the reaction is carried out at a temperature at about 90°Cto about 98⁰C.