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A regioselective copper catalyzed synthesis of benzimidazoles and azabenzimidazoles

A compound and heteroaryl technology, applied in the field of regioselective synthesis of compounds of formula I, can solve the problems of copper-catalyzed cross-coupling not showing universal applicability, poor cost-effectiveness, hindering optimization, etc.

Inactive Publication Date: 2010-03-31
SANOFI AVENTIS SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Furthermore, copper-catalyzed cross-couplings of 2-halo-nitroarenes and N-substituted amides have not shown general applicability
[0009] Limited regioselective access to N-substituted benzimidazoles or azabenzimidazoles often hampers optimization of potential pharmaceutical substances or substances with e.g. agricultural applications and is associated with poor cost-effectiveness

Method used

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  • A regioselective copper catalyzed synthesis of benzimidazoles and azabenzimidazoles
  • A regioselective copper catalyzed synthesis of benzimidazoles and azabenzimidazoles
  • A regioselective copper catalyzed synthesis of benzimidazoles and azabenzimidazoles

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preparation example Construction

[0188] During the preparation of compounds of formula I, it is often advantageous or necessary to introduce functional groups which reduce or prevent undesired or side reactions in the various synthetic steps in the form of precursor groups which are subsequently converted into the desired functional groups, or by means of suitable Protecting group strategies for synthetic problems to temporarily block functional groups. Such strategies are well known to those skilled in the art (see eg Greene and Wuts, Protective Groups in Organic Synthesis, Wiley, 1991 or P. Kocienski, Protecting Groups, Thieme 1994). As an example of a precursor group there may be mentioned the cyano group, which can be converted in a subsequent step into a carboxylic acid derivative or into an aminomethyl group by reduction. A protecting group can also have the meaning of a solid phase, and cleavage from a solid phase means removal of the protecting group. The use of such techniques is known to those skil...

Embodiment 1

[0209] Example 1: 2-Methyl-1-phenyl-1H-benzimidazole.

[0210]

[0211] A solution containing 2-iodonitrobenzene (125 mg, 0.5 mmol), N-phenylacetamide (81 mg, 0.6 mmol), CuI (4.8 mg, 0.025 mmol), N-methylethyl ether in anhydrous toluene (3 mL) The reaction tube of diamine (4.4 μL, 0.05 mmol), potassium phosphate (212 mg, 1 mmol) was purged with dry argon for 3 minutes. The mixture was then heated at 100 °C for 18 h. After cooling, the reaction was hydrolyzed with 3 mL of water and filtered through Varian cartridge Chem Elut 12198007, washing with ethyl acetate. The crude mixture was dissolved in 10 mL of glacial acetic acid and refluxed for 30 minutes in the presence of iron powder (279 mg, 5 mmol). The acid was removed under reduced pressure, the residue was suspended in saturated sodium bicarbonate solution and extracted with ethyl acetate. The obtained crude product was purified by preparative HPLC to obtain the title compound (82 mg, 73% yield) as a yellow solid. mp...

Embodiment 2

[0212] Example 2: 5-Chloro-2-methyl-1-phenyl-1H-benzimidazole.

[0213]

[0214] The title compound was prepared according to a method similar to that described in Example 1, using 4-chloro-1-bromo-2-nitrobenzene (118 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials , the title compound was obtained as a yellow solid (68 mg, 56% yield). mp 109-111℃. 1 HNMR (DMSO) δ2.52(s, 3H), 7.22(d, J=8.6Hz, 1H), 7.34(d, J=8.6Hz, 1H), 7.48-7.59(m, 5H), 7.86(s, 1H); 13 C NMR δ13.5, 112.2, 116.4, 123.9, 126.9, 127.9, 129.7, 130.1, 133.9, 138.5, 154.0, 157.0. HRMS (FAB): C 14 h 12 N 2 Cl[M+H + ], calculated value: 243.0689; measured value: 243.0684.

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Abstract

The present invention relates to a process for the regioselective synthesis of compounds of the formula (I), wherein R0; R1; R2; R3; R4; R5; A1; A2; A3; A4; Q and J have the meanings indicated in theclaims. The present invention provides a direct copper catalyzed regioselective process to a wide variety of unsymmetrical, multifunctional N / -substituted benzimidazoles or azabenzimidazoles of formula I starting from 2-halo-nitroarenes and N / -substituted amides. The process is useful for the production of pharmaceuticals, diagnostic agents, liquid crystals, polymers, herbicides, fungicidals, nematicidals, parasiticides, insecticides, acaricides and arthropodicides.

Description

field of invention [0001] The present invention relates to a process for the regioselective synthesis of compounds of formula I which are useful intermediates in the preparation of valuable pharmaceutically active ingredients, [0002] [0003] wherein R0; R1; R2; R3; R4; R5; A1; A2; A3; A4, Q and J have the meanings indicated below. Background of the invention [0004] The present invention relates to a direct copper-catalyzed regioselective process for the preparation of various asymmetric polyfunctional N-substituted benzimidazoles or azepines of formula I starting from 2-halo-nitroarenes and N-substituted amides Benzimidazole. [0005] Benzimidazoles play an important role in drug development and can be considered as dominant structures in drug research (D.A. Horton, G.T. Bourne, M.L. Smythe, Chem. Rev. 2003, 103, 893-930). This benzimidazole scaffold modulates interactions with multiple biological targets well documented by multiple reports of observed biological a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/08C07D235/16C07D235/18C07D401/04C07D471/04
CPCC07D235/16C07D471/04C07D235/18C07D235/08C07D401/04
Inventor J·阿朗索A·林登施密德M·纳扎雷M·乌尔曼N·哈兰O·勒克亚克
Owner SANOFI AVENTIS SA
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