1-(2,6-dichlorophenyl)-3H-indol-2-one

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

Procedure: To a stirred solution of [2-(2,6-Dichloro-phenylamino)-phenyl]-acetic acid] 2 (4.0 g, 0.01 mol, 1 eq) and N-BOC-Ethanolamine (2.39 g, 0.01 mol) in DCM (70 mL) was added DMAP (0.16 g, 0.001 mol) at rt. To this mixture was added DCC (5.5 g, 0.02 mol) in DCM (30 mL) drop-wise at 0-5° C. and resulting mixture was stirred at room temperature for 1 h. Reaction was monitored by TLC. After completion, reaction mixture was filtered and the solvent was removed under reduced pressure. Residue was dissolved in water (100 mL) and extracted with DCM (2×50 mL). Combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtained crude compound which was washed with hexane (2×20 mL), dried to get 6.0 g crude of Compound 4 and cyclized compound 1 as an off white solid. This mixture was used in the next step without any further purification: Mass: 439.3 (M++H). resulting mixture Reaction After completion, reaction mixture was filtered the solvent was removed under reduced pressure Residue was dissolved in water (100 mL) extracted with DCM (2×50 mL) Combined organic layer was dried over anhydrous Na2SO4 evaporated under reduced pressure to obtained crude compound which was washed with hexane (2×20 mL) dried

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1-(2,6-Dichloro-phenyl)-1,3-dihydro-indol-2-one 1 (10 g, 0.03 mol) in toluene (340 mL) was added aq. NaOH (2N, 34 mL)) at rt. The resulting mixture was stirred at 90° C. for 16 h. After completion, clear solution was cooled in an ice bath and acidified with con. HCl. The precipitated solid was filtered, washed with ethanol and dried under reduced pressure to get 9.0 g (84.4% yield) of Compound 2 as an off white solid. Used in the next step without any further purification; Mass: 294.1 (M−H); 1H-NMR (400 MHz, DMSO): 12.70 (s, 1H), 7.53-7.51 (d, J=8.0 Hz, 2H), 7.24-7.16 (m, 3H), 7.08-7.03 (m, 1H), 6.87-6.83 (m, 1H), 6.28-6.26 (d, J=7.8 Hz, 1H), 3.69 (s, 2H); 13C-NMR (400 MHz; DMSO): 173.86, 142.66, 137.11, 130.89, 130.04, 129.17, 127.51, 125.56, 123.89, 120.76, 115.95, 37.74. After completion, clear solution was cooled in an ice bath The precipitated solid was filtered washed with ethanol dried under reduced pressure

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1-(2,6-Dichloro-phenyl)-1,3-dihydro-indol-2-one 1 (10 g, 0.03 mol) in toluene (340 mL) was added aq. NaOH (2N, 34 mL)) at rt. The resulting mixture was stirred at 90° C. for 16 h. After completion, clear solution was cooled in an ice bath and acidified with con. HCl. The precipitated solid was filtered, washed with ethanol and dried under reduced pressure to get 9.0 g (84.4% yield) of Compound 2 as an off white solid. Used in the next step without any further purification; Mass: 294.1 (M−H); 1H-NMR (400 MHz, DMSO): 12.70 (s, 1H), 7.53-7.51 (d, J=8.0 Hz, 2H), 7.24-7.16 (m, 3H), 7.08-7.03 (m, 1H), 6.87-6.83 (m, 1H), 6.28-6.26 (d, J=7.8 Hz, 1H), 3.69 (s, 2H); 13C-NMR (400 MHz; DMSO): 173.86, 142.66, 137.11, 130.89, 130.04, 129.17, 127.51, 125.56, 123.89, 120.76, 115.95, 37.74. After completion, clear solution was cooled in an ice bath The precipitated solid was filtered washed with ethanol dried under reduced pressure

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

Procedure: 1.5 g sodium-[2-(2,6-dichloro-phenylamino)-phenyl]-acetate are dissolved in 6 ml of water, combined with 5.2 ml 1 N hydrochloric acid and the precipitated solid is suction filtered after stirring for 10 minutes. After drying in vacuo the solid is taken up in 6 ml of tetrahydrofuran, combined with 990 μl triethylamine and 1.17 g N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide-hydrochloride and stirred for 3 hours. Then it is divided between water and ethyl acetate, the aqueous phase is extracted twice with ethyl acetate and the combined organic phases are dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30 to 20:80). filtered After drying in vacuo the solid stirred for 3 hours the aqueous phase is extracted twice with ethyl acetate the combined organic phases are dried on magnesium sulphate the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30 to 20:80)

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

Procedure: 600 mg 1-(2,6-dichloro-phenyl)-1,3-dihydro-indol-2-one are dissolved in 5 ml concentrated sulphuric acid and cooled to 0° C. To this is added dropwise a solution of 160 μl concentrated nitric acid in 1 ml concentrated sulphuric acid. The mixture is stirred for 30 minutes and then added to 50 g ice. Then the mixture is stirred for 1 hour and the solid is suction filtered. After drying in vacuo the solid is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30 to 20:80). Then the mixture is stirred for 1 hour filtered After drying in vacuo the solid is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30 to 20:80)

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

Procedure: N-Hydroxysuccinimide (0.76 mmol) and DCC (0.76 mmol) are added to a solution of the corresponding diclofenac acid derivative (0.506 mmol) dissolved in 10 ml of dichloromethane. The mixture is stirred for 1 hour and monitored by TLC (EtOAc:He, 1:1). When completion of the reaction is detected, the mixture is filtered and the solvent is evaporated under reduced pressure. The crude product is purified by column chromatography to afford the pure diclofenac amide derivative. the mixture is filtered the solvent is evaporated under reduced pressure The crude product is purified by column chromatography

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

Procedure: To a stirred solution of [2-(2,6-Dichloro-phenylamino)-phenyl]-acetic acid] 2 (4.0 g, 0.01 mol, 1 eq) and N—BOC-Ethanolamine (2.39 g, 0.01 mol) in DCM (70 mL) was added DMAP (0.16 g, 0.001 mol) at rt. To this mixture was added DCC (5.5 g, 0.02 mol) in DCM (30 mL) drop-wise at 0-5° C. and resulting mixture was stirred at room temperature for 1 h. Reaction was monitored by TLC. After completion, reaction mixture was filtered and the solvent was removed under reduced pressure. Residue was dissolved in water (100 mL) and extracted with DCM (2×50 mL). Combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtained crude compound which was washed with hexane (2×20 mL), dried to get 6.0 g crude of Compound 4 and cyclized compound 1 as an off white solid. This mixture was used in the next step without any further purification; Mass: 439.3 (M++H). resulting mixture Reaction After completion, reaction mixture was filtered the solvent was removed under reduced pressure Residue was dissolved in water (100 mL) extracted with DCM (2×50 mL) Combined organic layer was dried over anhydrous Na2SO4 evaporated under reduced pressure to obtained crude compound which was washed with hexane (2×20 mL) dried

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1-(2,6-Dichloro-phenyl)-1,3-dihydro-indol-2-one 1 (10 g, 0.03 mol) in toluene (340 mL) was added aq. NaOH (2N, 34 mL)) at rt. The resulting mixture was stirred at 90° C. for 16 h. After completion, clear solution was cooled in an ice bath and acidified with con. HCl. The precipitated solid was filtered, washed with ethanol and dried under reduced pressure to get 9.0 g (84.4% yield) of Compound 2 as an off white solid. Used in the next step without any further purification; Mass: 294.1 (M−H); 1H-NMR (400 MHz, DMSO): 12.70 (s, 1H), 7.53-7.51 (d, J=8.0 Hz, 2H), 7.24-7.16 (m, 3H), 7.08-7.03 (m, 1H), 6.87-6.83 (m, 1H), 6.28-6.26 (d, J=7.8 Hz, 1H), 3.69 (s, 2H); 13C-NMR (400 MHz; DMSO): 173.86, 142.66, 137.11, 130.89, 130.04, 129.17, 127.51, 125.56, 123.89, 120.76, 115.95, 37.74. After completion, clear solution was cooled in an ice bath The precipitated solid was filtered washed with ethanol dried under reduced pressure

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

Procedure: N-Hydroxysuccinimide (0.76 mmol) and DCC (0.76 mmol) are added to a solution of the corresponding diclofenac acid derivative (0.506 mmol) dissolved in 10 ml of dichloromethane. The mixture is stirred for 1 hour and monitored by TLC (EtOAc:He, 1:1). When completion of the reaction is detected, the mixture is filtered and the solvent is evaporated under reduced pressure. The crude product is purified by column chromatography to afford the pure diclofenac amide derivative. the mixture is filtered the solvent is evaporated under reduced pressure The crude product is purified by column chromatography

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

Procedure: To a stirred solution of [2-(2,6-Dichloro-phenylamino)-phenyl]-acetic acid] 2 (4.0 g, 0.01 mol, 1 eq) and N-BOC-Ethanolamine (2.39 g, 0.01 mol) in DCM (70 mL) was added DMAP (0.16 g, 0.001 mol) at rt. To this mixture was added DCC (5.5 g, 0.02 mol) in DCM (30 mL) drop-wise at 0-5° C. and resulting mixture was stirred at room temperature for 1 h. Reaction was monitored by TLC. After completion, reaction mixture was filtered and the solvent was removed under reduced pressure. Residue was dissolved in water (100 mL) and extracted with DCM (2×50 mL). Combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtained crude compound which was washed with hexane (2×20 mL), dried to get 6.0 g crude of Compound 4 and cyclized compound 1 as an off white solid. This mixture was used in the next step without any further purification: Mass: 439.3 (M++H). resulting mixture Reaction After completion, reaction mixture was filtered the solvent was removed under reduced pressure Residue was dissolved in water (100 mL) extracted with DCM (2×50 mL) Combined organic layer was dried over anhydrous Na2SO4 evaporated under reduced pressure to obtained crude compound which was washed with hexane (2×20 mL) dried

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1-(2,6-Dichloro-phenyl)-1,3-dihydro-indol-2-one 1 (10 g, 0.03 mol) in toluene (340 mL) was added aq. NaOH (2N, 34 mL)) at rt. The resulting mixture was stirred at 90° C. for 16 h. After completion, clear solution was cooled in an ice bath and acidified with con. HCl. The precipitated solid was filtered, washed with ethanol and dried under reduced pressure to get 9.0 g (84.4% yield) of Compound 2 as an off white solid. Used in the next step without any further purification; Mass: 294.1 (M−H); 1H-NMR (400 MHz, DMSO): 12.70 (s, 1H), 7.53-7.51 (d, J=8.0 Hz, 2H), 7.24-7.16 (m, 3H), 7.08-7.03 (m, 1H), 6.87-6.83 (m, 1H), 6.28-6.26 (d, J=7.8 Hz, 1H), 3.69 (s, 2H); 13C-NMR (400 MHz; DMSO): 173.86, 142.66, 137.11, 130.89, 130.04, 129.17, 127.51, 125.56, 123.89, 120.76, 115.95, 37.74. After completion, clear solution was cooled in an ice bath The precipitated solid was filtered washed with ethanol dried under reduced pressure