2-methylsulfonylaniline

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

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methylsulfonylaniline (48 g, 0.28 mole), was added portion-wise with stirring to 365 mL of water, 250 mL of conc. HCl and 60 mL of HOAc. The mixture was cooled to 50° C. and sodium nitrite (22.3 g; 0.32 mole) dissolved in 250 mL water, was added drop-wise with stirring maintaining the temperature between 0-5° C. After complete addition of sodium nitrite, the resulting solution was stirred for 30 minutes at 0-5° C. Sulfur dioxide was bubbled into 200 mL of glacial acetic acid at room temperature for 10 minutes CuCl2·2H2O (11 g; 0.06 mole) and CuCl (3.7 g; 0.037 mole) were added to the HOAc and cooled to 10° C. Sulfur dioxide was bubbled through the suspension for an additional 15 minutes and the diazotized amine was added portionwise with stirring keeping the temperature between 0-5° C. Sulfur dioxide was bubbled in continuously until the diazotized amine was added completely. After the complete addition of the diazotized amine, bubbling of SO2 was stopped and the green suspension was stirred at 0-5° C. for 3 hours. At the end of 3 hours, the suspension was diluted with water (300 mL), filtered and the solid washed three times with 50 mL of water. The product was dried at room temperature in vacuum (30 in. Hg) to give 46 g of 2-methylsulfonylbenzenesulfonyl chloride (61% yield) as a white solid. mp 135-137° C. (lit. 133-135° C.). 1H NMR (CDCl3) δ 8.3-8.6 (m, 2H), 7.87-8.02 (m, 2H), 3.41 (s, 3H). 13C NMR (CDCl3) δ 142.94, 139.24, 136.61, 135.22, 133.58, 132.13, 45.49. CIMS (m/e) 255 (M+H+, 100%). was added drop-wise maintaining the temperature between 0-5° C the resulting solution was stirred for 30 minutes at 0-5° C cooled to 10° C Sulfur dioxide was bubbled through the suspension for an additional 15 minutes the diazotized amine was added portionwise with stirring between 0-5° C Sulfur dioxide was bubbled in continuously until the diazotized amine was added completely After the complete addition of the diazotized amine bubbling of SO2 the green suspension was stirred at 0-5° C. for 3 hours At the end of 3 hours, the suspension was diluted with water (300 mL) filtered the solid washed three times with 50 mL of water The product was dried at room temperature in vacuum (30 in. Hg)

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methylsulfonylaniline (6.0 g; 0.035 mole) was added portionwise, with stirring, to a mixture of 30 mL of water and 30 mL of HCl. The mixture was cooled to 5° C. and sodium nitrite (2.7 g; 0.039 mole) dissolved in water (7 mL) was added dropwise maintaining the temperature between 0-5° C. After complete addition of sodium nitrite, the resulting solution was stirred at 0-5° C. for 30 minutes Sulfur dioxide was bubbled into 18 mL of HOAc for 14 min at room temperature. CuCl (0.8 g; 0.008 mole) was added and cooled to 10° C. Sulfur dioxide was bubbled through the suspension for an additional 15 min and the diazotized amine was added portionwise maintaining the temperature between 0-5° C. After the complete addition of diazotized amine, bubbling of SO2 was stopped and the green suspension was stirred at 0-5° C. for 3 hours. At the end of 3 hours, the suspension was diluted with 50 mL of water, filtered and washed three times with 10 mL of water to give, after drying in vacuum (30 in. Hg), 6.4 g (71% yield) of 2-methylsulfonylbenzenesulfonyl chloride which was characterized by its melting point and spectral data. mp 135-137° C. (lit. 133-135° C.). 1H NMR (CDCl3) δ 8.3-8.6 (m, 2H), 7.87-8.02 (m, 2H), 3.41 (s, 3H). 13C NMR (CDCl3) δ 142.94, 139.24, 136.61, 135.22, 133.58, 132.13, 45.49. CIMS (m/e) 255 (M+H+, 100%). was added dropwise maintaining the temperature between 0-5° C was bubbled into 18 mL of HOAc for 14 min at room temperature cooled to 10° C Sulfur dioxide was bubbled through the suspension for an additional 15 min the diazotized amine was added portionwise maintaining the temperature between 0-5° C After the complete addition of diazotized amine bubbling of SO2 At the end of 3 hours, the suspension was diluted with 50 mL of water filtered washed three times with 10 mL of water to give

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methylsulfonylnitrobenzene (13.0 g , 0.065 mol) was suspended in MeOH (140 mL) and 2N H2SO4 (60 mL). 6% Pd/C catalyst (50% wet; 3 g) was added to the suspension and it was hydrogenated at 40 psi in a Parr shaker for 4 hours. The solution was filtered, the catalyst washed twice with 10 mL of MeOH and concentrated on the rotary evaporator to a volume of 80 mL. The suspension was cooled to 5° C. with stirring and 15 mL of aqueous 10 N sodium hydroxide was added and stirred for 30 minutes at 5° C. The solid was filtered, washed with water and dried at 40° C. in vacuum (30 in. Hg) to give 10.5 g (95% yield) of 2-methylsulfonylaniline. The solution was filtered the catalyst washed twice with 10 mL of MeOH concentrated on the rotary evaporator to a volume of 80 mL 15 mL of aqueous 10 N sodium hydroxide was added stirred for 30 minutes at 5° C The solid was filtered washed with water dried at 40° C. in vacuum (30 in. Hg)

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

Procedure: 2-Methylsulfonyinitrobenzene (6.0g, 0.03 mol) was suspended in absolute ethanol (60 mL). 6% Pd/C catalyst (50% wet; 1.01 g) was added and the suspension was hydrogenated in a Parr shaker at 40 psi for 16 hours. The catalyst was then filtered over a pad of infusorial earth and washed with ethanol (2×10 ml). The filtrate was concentrated to dryness on a rotary evaporator. 4.94 g (96% yield) of the product was obtained as white crystals. mp 82-84° C. 1H NMR (CDCl3) δ 7.7 (dd, 1H), 7.2-7.3 (m, 1H), 6.5-6.8 (m, 2H), 5.04 (bs, 2H), 3.07 (s, 3H); CIMS (m/e) 172 (M+H+, 100%). The catalyst was then filtered over a pad of infusorial earth washed with ethanol (2×10 ml) The filtrate was concentrated to dryness on a rotary evaporator

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

Procedure: 2-Methylsulfonyinitrobenzene (6.0g, 0.03 mol) was suspended in absolute ethanol (60 mL). 6% Pd/C catalyst (50% wet; 1.01 g) was added and the suspension was hydrogenated in a Parr shaker at 40 psi for 16 hours. The catalyst was then filtered over a pad of infusorial earth and washed with ethanol (2×10 ml). The filtrate was concentrated to dryness on a rotary evaporator. 4.94 g (96% yield) of the product was obtained as white crystals. mp 82-84° C. 1H NMR (CDCl3) δ 7.7 (dd, 1H), 7.2-7.3 (m, 1H), 6.5-6.8 (m, 2H), 5.04 (bs, 2H), 3.07 (s, 3H); CIMS (m/e) 172 (M+H+, 100%). The catalyst was then filtered over a pad of infusorial earth washed with ethanol (2×10 ml) The filtrate was concentrated to dryness on a rotary evaporator

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

Procedure: (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (234.0 mg, 1.007 mmol) and 2-methanesulfonyl-phenylamine; hydrochloride (220.0 mg, 1.059 mmol) with 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (105.0 mg, 0.1815 mmol) as the ligand in a manner analogous to Step 2d. The reaction product was isolated as a pale yellow solid (0.115 g, 35%). MP=180-182° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (s, 1H), 8.18 (d, J=6.7 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.60-7.54 (m, 1H), 7.51 (d, J=8.2, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.18 (t, J=7.2 Hz, 1H), 6.98 (t, J=7.2 Hz, 1H), 3.12 (s, 3H). MS=323, 325 (MH)+.

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

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

Procedure: To a cooled, stirred suspension of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.961 g, 4.51 mmol) and copper(II)chloride dihydrate (0.20 g, 1.2 mmol) in 12 M of hydrochloric acid (10.0 mL) at 5° C. was added dropwise a solution of sodium nitrite (0.37 g, 5.4 mmol) in water (2 mL). Gentle gas evolution was noted. The mixture was stirred for 30 minutes at 5° C. then at room temperature for 18 hours. The yellow mixture was diluted with water (80 mL) and the resulting precipitate was filtered, rinsed with water and dried in-the-air. 8-Bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine was isolated as a pale yellow solid (0.947 g, 90%) and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.98 (d, J=6.9 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.22 (t, J=7.0 Hz, 1H). MS=232, 234, 236 (MH)+. 68b) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (234.0 mg, 1.007 mmol) and 2-methanesulfonyl-phenylamine; hydrochloride (220.0 mg, 1.059 mmol) with 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (105.0 mg, 0.1815 mmol) as the ligand in a manner analogous to Step 2d. The reaction product was isolated as a pale yellow solid (0.115 g, 35%). MP=180-182° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (s, 1H), 8.18 (d, J=6.7 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.60-7.54 (m, 1H), 7.51 (d, J=8.2, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.18 (t, J=7.2 Hz, 1H), 6.98 (t, J=7.2 Hz, 1H), 3.12 (s, 3H). MS=323, 325 (MH)+. 68c) N(8)-(2-Methanesulfonyl-phenyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine (95.0 mg, 0.294 mmol) and 3-(4-methylpiperazin-1-yl)aniline (70.0 mg, 0.366 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (32.0 mg, 0.0585 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a light brown foam (0.077 g, 55%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (s, 1H), 8.11 (d, J=6.5, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.58-7.51 (m, 2H), 7.43 (s, 1H), 7.30-7.25 (m, 1H), 7.20 (t, J=8.1 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.84-6.78 (m, 2H), 6.57 (d, J=8.1 Hz, 1H), 3.33-3.25 (m, 4H), 3.13 (s, 3H), 2.70-2.57 (m, 4H), 2.39 (s, 3H). MS=478 (MH)+. was used without further purification

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methylsulfonylaniline (6.0 g; 0.035 mole) was added portionwise, with stirring, to a mixture of 30 mL of water and 30 mL of HCl. The mixture was cooled to 5° C. and sodium nitrite (2.7 g; 0.039 mole) dissolved in water (7 mL) was added dropwise maintaining the temperature between 0-5° C. After complete addition of sodium nitrite, the resulting solution was stirred at 0-5° C. for 30 minutes Sulfur dioxide was bubbled into 18 mL of HOAc for 14 min at room temperature. CuCl (0.8 g; 0.008 mole) was added and cooled to 10° C. Sulfur dioxide was bubbled through the suspension for an additional 15 min and the diazotized amine was added portionwise maintaining the temperature between 0-5° C. After the complete addition of diazotized amine, bubbling of SO2 was stopped and the green suspension was stirred at 0-5° C. for 3 hours. At the end of 3 hours, the suspension was diluted with 50 mL of water, filtered and washed three times with 10 mL of water to give, after drying in vacuum (30 in. Hg), 6.4 g (71% yield) of 2-methylsulfonylbenzenesulfonyl chloride which was characterized by its melting point and spectral data. mp 135-137° C. (lit. 133-135° C.). 1H NMR (CDCl3) δ 8.3-8.6 (m, 2H), 7.87-8.02 (m, 2H), 3.41 (s, 3H). 13C NMR (CDCl3) δ 142.94, 139.24, 136.61, 135.22, 133.58, 132.13, 45.49. CIMS (m/e) 255 (M+H+, 100%). was added dropwise maintaining the temperature between 0-5° C was bubbled into 18 mL of HOAc for 14 min at room temperature cooled to 10° C Sulfur dioxide was bubbled through the suspension for an additional 15 min the diazotized amine was added portionwise maintaining the temperature between 0-5° C After the complete addition of diazotized amine bubbling of SO2 At the end of 3 hours, the suspension was diluted with 50 mL of water filtered washed three times with 10 mL of water to give

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methylsulfonylaniline (48 g, 0.28 mole), was added portion-wise with stirring to 365 mL of water, 250 mL of conc. HCl and 60 mL of HOAc. The mixture was cooled to 50° C. and sodium nitrite (22.3 g; 0.32 mole) dissolved in 250 mL water, was added drop-wise with stirring maintaining the temperature between 0-5° C. After complete addition of sodium nitrite, the resulting solution was stirred for 30 minutes at 0-5° C. Sulfur dioxide was bubbled into 200 mL of glacial acetic acid at room temperature for 10 minutes CuCl2·2H2O (11 g; 0.06 mole) and CuCl (3.7 g; 0.037 mole) were added to the HOAc and cooled to 10° C. Sulfur dioxide was bubbled through the suspension for an additional 15 minutes and the diazotized amine was added portionwise with stirring keeping the temperature between 0-5° C. Sulfur dioxide was bubbled in continuously until the diazotized amine was added completely. After the complete addition of the diazotized amine, bubbling of SO2 was stopped and the green suspension was stirred at 0-5° C. for 3 hours. At the end of 3 hours, the suspension was diluted with water (300 mL), filtered and the solid washed three times with 50 mL of water. The product was dried at room temperature in vacuum (30 in. Hg) to give 46 g of 2-methylsulfonylbenzenesulfonyl chloride (61% yield) as a white solid. mp 135-137° C. (lit. 133-135° C.). 1H NMR (CDCl3) δ 8.3-8.6 (m, 2H), 7.87-8.02 (m, 2H), 3.41 (s, 3H). 13C NMR (CDCl3) δ 142.94, 139.24, 136.61, 135.22, 133.58, 132.13, 45.49. CIMS (m/e) 255 (M+H+, 100%). was added drop-wise maintaining the temperature between 0-5° C the resulting solution was stirred for 30 minutes at 0-5° C cooled to 10° C Sulfur dioxide was bubbled through the suspension for an additional 15 minutes the diazotized amine was added portionwise with stirring between 0-5° C Sulfur dioxide was bubbled in continuously until the diazotized amine was added completely After the complete addition of the diazotized amine bubbling of SO2 the green suspension was stirred at 0-5° C. for 3 hours At the end of 3 hours, the suspension was diluted with water (300 mL) filtered the solid washed three times with 50 mL of water The product was dried at room temperature in vacuum (30 in. Hg)

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methylsulfonylnitrobenzene (13.0 g , 0.065 mol) was suspended in MeOH (140 mL) and 2N H2SO4 (60 mL). 6% Pd/C catalyst (50% wet; 3 g) was added to the suspension and it was hydrogenated at 40 psi in a Parr shaker for 4 hours. The solution was filtered, the catalyst washed twice with 10 mL of MeOH and concentrated on the rotary evaporator to a volume of 80 mL. The suspension was cooled to 5° C. with stirring and 15 mL of aqueous 10 N sodium hydroxide was added and stirred for 30 minutes at 5° C. The solid was filtered, washed with water and dried at 40° C. in vacuum (30 in. Hg) to give 10.5 g (95% yield) of 2-methylsulfonylaniline. The solution was filtered the catalyst washed twice with 10 mL of MeOH concentrated on the rotary evaporator to a volume of 80 mL 15 mL of aqueous 10 N sodium hydroxide was added stirred for 30 minutes at 5° C The solid was filtered washed with water dried at 40° C. in vacuum (30 in. Hg)