2,4,6-trichlorobenzoyl chloride

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid (from Example 1, 50 mg, 0.17 mmol) and triethylamine (0.07 mL, 0.52 mmol) in toluene (5 mL), previously cooled to 0° C. was treated with 2,4,6-trichlorobenzoyl chloride (0.03 mL, 0.19 mmol) and the mixture was stirred at 0° C. After 1 h, 2-aminopyridine (20 mg, 0.21 mmol) and 4-dimethylaminopyridine (5 mg, 0.035 mmol) were added and the stirring was continued for 1 h at 0° C. The reaction was checked for completion, then it was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (Biotage Flash 12M column, 80/20 hexanes/ethyl acetate) to give rac-2-cyclopentyloxy-2-(3,4-dichloro-phenyl)-N-pyridin-2-yl-acetamide (48 mg, 76% yield) as a white foam: EI-HRMS m/e calculated for C18H18N2O2Cl2 (M+) 364.0745, found 364.0746. the stirring was continued for 1 h at 0° C extracted with dichloromethane (3×10 mL) The combined organic extracts were dried over sodium sulfate filtered concentrated in vacuo The product was purified by chromatography (Biotage Flash 12M column, 80/20 hexanes/ethyl acetate)

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

Procedure: To a solution of 2-ethoxy-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (4.0 g) and triethylamine (1.3 mL) in THF (50 mL) was added dropwise 2,4,6-trichlorobenzoyl chloride (1.4 mL) under ice-cooling. After stirring at room temperature for 12 hrs., insoluble material was filtered off and the filtrate was concentrated. The residue was dissolved in methylene chloride (50 mL) and 5-oxotetrahydro-2-furanyl (0.67 g) and N,N-dimethylaminopyridine (1.0 g) were added under ice-cooling. After stirring at room temperature for 4 hrs., the reaction mixture was diluted with chloroform (150 mL), washed with water, saturated aqueous sodium hydrogen carbonate, 1 N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound (0.16 g, 3.3%) as a colorless solid. cooling , insoluble material was filtered off the filtrate was concentrated The residue was dissolved in methylene chloride (50 mL) 5-oxotetrahydro-2-furanyl (0.67 g) and N,N-dimethylaminopyridine (1.0 g) were added under ice- cooling After stirring at room temperature for 4 hrs , the reaction mixture was diluted with chloroform (150 mL) washed with water, saturated aqueous sodium hydrogen carbonate, 1 N hydrochloric acid and saturated brine dried over anhydrous sodium sulfate concentrated The residue was purified by silica gel column chromatography

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

Procedure: To a solution of 2-ethoxy-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (4.0 g) and triethylamine (1.3 mL) in THF (50 mL) was added dropwise 2,4,6-trichlorobenzoyl chloride (1.4 mL) under ice-cooling. After stirring at room temperature for 12 hrs., insoluble material was filtered off and the filtrate was concentrated. The residue was dissolved in methylene chloride (50 mL) and 5-oxotetrahydro-2-furanyl (0.67 g) and N,N-dimethylaminopyridine (1.0 g) were added under ice-cooling. After stirring at room temperature for 4 hrs., the reaction mixture was diluted with chloroform (150 mL), washed with water, saturated aqueous sodium hydrogen carbonate, 1 N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound (0.16 g, 3.3%) as a colorless solid. cooling , insoluble material was filtered off the filtrate was concentrated The residue was dissolved in methylene chloride (50 mL) 5-oxotetrahydro-2-furanyl (0.67 g) and N,N-dimethylaminopyridine (1.0 g) were added under ice- cooling After stirring at room temperature for 4 hrs , the reaction mixture was diluted with chloroform (150 mL) washed with water, saturated aqueous sodium hydrogen carbonate, 1 N hydrochloric acid and saturated brine dried over anhydrous sodium sulfate concentrated The residue was purified by silica gel column chromatography

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

Procedure: A mixture of 4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}butanoic acid (42c) (0.049 g, 0.1 mmol), 2,4,6-trichlorobenzoyl chloride (0.244 g, 1 mmol), 4-dimethylaminopyridine (0.122 g, 1 mmol) and methanesulfonamide (0.019 g, 0.2 mmol) in dichloromethane was stirred at room temperature for 20 hours. The mixture was concentrated and chromatographed (dichloromethane:acetone, 80:20) to yield N-(4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}-butanoyl)-methanesulfonamide (42f) [RD157] (0.053 g, 0.094 mmol, 94%), the structure of which is illustrated in Formula 8, as a white powder. The mixture was concentrated chromatographed (dichloromethane:acetone, 80:20)

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

Procedure: A mixture of 4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}butanoic acid (42c) (0.049 g, 0.1 mmol), 2,4,6-trichlorobenzoyl chloride (0.244 g, 1 mmol), 4-dimethylaminopyridine (0.122 g, 1 mmol) and methanesulfonamide (0.019 g, 0.2 mmol) in dichloromethane was stirred at room temperature for 20 hours. The mixture was concentrated and chromatographed (dichloromethane:acetone, 80:20) to yield N-(4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}-butanoyl)-methanesulfonamide (42f) [RD157] (0.053 g, 0.094 mmol, 94%), the structure of which is illustrated in Formula 8, as a white powder. The mixture was concentrated chromatographed (dichloromethane:acetone, 80:20)