methyl 3-chloro-5-fluoro-4-hydroxybenzoate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), and 3-chloro-5-fluoro-4-hydroxy-benzoic acid methyl ester (CAS RN 369-15-3) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30) to give the desired compound as a colorless foam (74%). MS (Turbo Spray): 577.1 [M+H]. The residue was purified by silica gel chromatography eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), and 3-chloro-5-fluoro-4-hydroxy-benzoic acid methyl ester (CAS RN 369-15-3) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30) to give the desired compound as a colorless foam (74%). MS (Turbo Spray): 577.1 [M+H]. The residue was purified by silica gel chromatography eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), and 3-chloro-5-fluoro-4-hydroxy-benzoic acid methyl ester (CAS RN 369-15-3) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30) to give the desired compound as a colorless foam (74%). MS (Turbo Spray): 577.1 [M+H]. The residue was purified by silica gel chromatography eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(chloromethyl)-5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (154 mg, 0.39 mmol), methyl 3-chloro-5-fluoro-4-hydroxybenzoate (118 mg 0.57 mmol), potassium carbonate (79 mg, 0.57 mmol), and 18-crown-6 (11 mg, 0.04 mmol) in CH3CN (4 mL) was heated 8 h at 60° C. After cooling, the reaction mixture was filtered, combined with water and DCM, and then extracted further with DCM. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The material was purified by chromatography (silica, 0-70% EtOAc/Hex) to give methyl 3-chloro-4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)-5-fluorobenzoate as a white solid (150 mg, 68% yield). MS (EI) m/z 567.3 [M+H]+. After cooling the reaction mixture was filtered extracted further with DCM The combined extracts were washed with brine dried over Na2SO4 concentrated in vacuo The material was purified by chromatography (silica, 0-70% EtOAc/Hex)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(chloromethyl)-5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (154 mg, 0.39 mmol), methyl 3-chloro-5-fluoro-4-hydroxybenzoate (118 mg 0.57 mmol), potassium carbonate (79 mg, 0.57 mmol), and 18-crown-6 (11 mg, 0.04 mmol) in CH3CN (4 mL) was heated 8 h at 60° C. After cooling, the reaction mixture was filtered, combined with water and DCM, and then extracted further with DCM. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The material was purified by chromatography (silica, 0-70% EtOAc/Hex) to give methyl 3-chloro-4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)-5-fluorobenzoate as a white solid (150 mg, 68% yield). MS (EI) m/z 567.3 [M+H]+. After cooling the reaction mixture was filtered extracted further with DCM The combined extracts were washed with brine dried over Na2SO4 concentrated in vacuo The material was purified by chromatography (silica, 0-70% EtOAc/Hex)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), and 3-chloro-5-fluoro-4-hydroxy-benzoic acid methyl ester (CAS RN 369-15-3) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30) to give the desired compound as a colorless foam (74%). MS (Turbo Spray): 577.1 [M+H]. The residue was purified by silica gel chromatography eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30)