5-chloro-7-methyl-1H-indole-2,3-dione

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

Procedure: To a suspension of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see PCT Patent Publication WO 03/015519 for preparation) (97.6% purity, 13.02 g, 42 mmol) and 5-chloro-7-methylindoline-2,3-dione (K. Tsuji et al., Bioorg. Med. Chem. Letters, 2002, 12(17), pp 2427-2430) (7.82 g, 40 mmol) in dry acetonitrile (50 mL) was added 3-picoline (11.9 g, 127 mmol). The mixture was cooled to 0° C., and then methanesulfonyl chloride (6.87 g, 60 mmol) was added dropwise at 0-10° C. After stirring 5 minutes at this temperature, the mixture was warmed to room temperature for 20 hours. The precipitated solids were filtered, washed with acetonitrile (3×5 mL), and dried under nitrogen to afford the title product, a compound of the present invention, as a yellow powder, 14.90 g (77.6% yield), m.p. 173-177° C. (decomp.). the mixture was warmed to room temperature for 20 hours The precipitated solids were filtered washed with acetonitrile (3×5 mL) dried under nitrogen

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

Procedure: To a suspension of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see PCT Patent Publication WO 03/015519 for preparation) (97.6% purity, 13.02 g, 42 mmol) and 5-chloro-7-methylindoline-2,3-dione (K. Tsuji et al., Bioorg. Med. Chem. Letters, 2002, 12(17), pp 2427-2430) (7.82 g, 40 mmol) in dry acetonitrile (50 mL) was added 3-picoline (11.9 g, 127 mmol). The mixture was cooled to 0° C., and then methanesulfonyl chloride (6.87 g, 60 mmol) was added dropwise at 0-10° C. After stirring 5 minutes at this temperature, the mixture was warmed to room temperature for 20 hours. The precipitated solids were filtered, washed with acetonitrile (3×5 mL), and dried under nitrogen to afford the title product, a compound of the present invention, as a yellow powder, 14.90 g (77.6% yield), m.p. 173-177° C. (decomp.). the mixture was warmed to room temperature for 20 hours The precipitated solids were filtered washed with acetonitrile (3×5 mL) dried under nitrogen

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

Procedure: To a suspension of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see PCT Patent Publication WO 03/015519 for preparation) (97.6% purity, 3.25 g, 10.5 mmol) and 5-chloro-7-methylindoline-2,3-dione (K. Tsuji et al., Bioorg. Med. Chem. Letters, 2002, 12(17), pp 2427-2430) (1.96 g, 10.0 mmol) in dry acetonitrile (12 mL) was added 3-picoline (2.60 g, 28 mmol). The mixture was cooled to 0° C., and then methanesulfonyl chloride (1.48 g, 12.9 mmol) was added dropwise at 0-10° C. After stirring 5 minutes at this temperature, the mixture was warmed to room temperature for 2 hours. Then additional quantities of 3-picoline (0.37 g, 4.0 mmol) and methanesulfonyl chloride (0.24 g, 2.1 mmol) were added, and stirring was continued at room temperature for 3 hours. The mixture was cooled to 0° C., water (6 mL) was added dropwise, and stirring at 0-5° C. was continued for 1 hour. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3×3 mL), and dried under nitrogen to afford the 3-picoline salt of the title compound as a light green solid, 1.23 g. the mixture was warmed to room temperature for 2 hours stirring was continued at room temperature for 3 hours The mixture was cooled to 0° C. stirring at 0-5° C. was continued for 1 hour Then the mixture was filtered the solids were washed with 2:1 acetonitrile-water (3×3 mL) dried under nitrogen

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

Procedure: The 5-chloro-7-methyl-1H-indole-2,3-dione (25.0 g, 0.13 mol), potassium hydroxide (8.4 g, 0.15 mmol) and 30% hydrogen peroxide (21.6 g, 0.18 mol) were mixed together in methanol (300 mL) at 0° C. for 2 h followed by 16 h at room temperature. The solution was poured into ethyl acetate (500 mL) and extracted with I N hydrochloric acid (3×200 mL) followed by brine (1×50 mL). The solution was dried over sodium sulfate and solvent removed at reduced pressure. The 2-amino-5-chloro-3-methylbenzoic acid (18.0 g, 0.10 mmol) was isolated as a yellow solid (75% yield). HRMS m/z 185.0238; calcd 185.0244. extracted with I N hydrochloric acid (3×200 mL) The solution was dried over sodium sulfate and solvent removed at reduced pressure

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

Procedure: To a suspension of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see PCT Patent Publication WO 03/015519 for preparation) (97.6% purity, 13.02 g, 42 mmol) and 5-chloro-7-methylindoline-2,3-dione (K. Tsuji et al., Bioorg. Med. Chem. Letters, 2002, 12(17), pp 2427-2430) (7.82 g, 40 mmol) in dry acetonitrile (50 mL) was added 3-picoline (11.9 g, 127 mmol). The mixture was cooled to 0° C., and then methanesulfonyl chloride (6.87 g, 60 mmol) was added dropwise at 0-10° C. After stirring 5 minutes at this temperature, the mixture was warmed to room temperature for 20 hours. The precipitated solids were filtered, washed with acetonitrile (3×5 mL), and dried under nitrogen to afford the title product, a compound of the present invention, as a yellow powder, 14.90 g (77.6% yield), m.p. 173-177° C. (decomp.). the mixture was warmed to room temperature for 20 hours The precipitated solids were filtered washed with acetonitrile (3×5 mL) dried under nitrogen

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

Procedure: To a suspension of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see PCT Patent Publication WO 03/015519 for preparation) (97.6% purity, 3.25 g, 10.5 mmol) and 5-chloro-7-methylindoline-2,3-dione (K. Tsuji et al., Bioorg. Med. Chem. Letters, 2002, 12(17), pp 2427-2430) (1.96 g, 10.0 mmol) in dry acetonitrile (12 mL) was added 3-picoline (2.60 g, 28 mmol). The mixture was cooled to 0° C., and then methanesulfonyl chloride (1.48 g, 12.9 mmol) was added dropwise at 0-10° C. After stirring 5 minutes at this temperature, the mixture was warmed to room temperature for 2 hours. Then additional quantities of 3-picoline (0.37 g, 4.0 mmol) and methanesulfonyl chloride (0.24 g, 2.1 mmol) were added, and stirring was continued at room temperature for 3 hours. The mixture was cooled to 0° C., water (6 mL) was added dropwise, and stirring at 0-5° C. was continued for 1 hour. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3×3 mL), and dried under nitrogen to afford the 3-picoline salt of the title compound as a light green solid, 1.23 g. the mixture was warmed to room temperature for 2 hours stirring was continued at room temperature for 3 hours The mixture was cooled to 0° C. stirring at 0-5° C. was continued for 1 hour Then the mixture was filtered the solids were washed with 2:1 acetonitrile-water (3×3 mL) dried under nitrogen

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

Procedure: The 5-chloro-7-methyl-1H-indole-2,3-dione (25.0 g, 0.13 mol), potassium hydroxide (8.4 g, 0.15 mmol) and 30% hydrogen peroxide (21.6 g, 0.18 mol) were mixed together in methanol (300 mL) at 0° C. for 2 h followed by 16 h at room temperature. The solution was poured into ethyl acetate (500 mL) and extracted with I N hydrochloric acid (3×200 mL) followed by brine (1×50 mL). The solution was dried over sodium sulfate and solvent removed at reduced pressure. The 2-amino-5-chloro-3-methylbenzoic acid (18.0 g, 0.10 mmol) was isolated as a yellow solid (75% yield). HRMS m/z 185.0238; calcd 185.0244. extracted with I N hydrochloric acid (3×200 mL) The solution was dried over sodium sulfate and solvent removed at reduced pressure