| 128g |
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 3.5h; |
2 Synthesis of sodium[(4-tert-butylphenyl)sulfonyl][4-chloro-2-(1-oxidoisonicotinoyl)phenyl]azanide (Sodium Salt of Compound B)
[0125] Sodium hydride (60%, 5.97 g) was washed 3 times with dehydrated hexane (30 mL), dehydrated dimethylformamide (31 mL) was added, and a suspension of 4-tert-butyl-N-[4-chloro-2-(1-oxidoisonicctinoyl)phenyl]benzenesulfonamide (61.0 g) in dehydrated dimethylformamide (300 ml) was added at 0° C. The mixture was warmed to room temperature, and stirred for 3.5 hr. The mixture was filtered, washed with dehydrated dimethylformamide, diluted with dichloromethane (DCM) (2700 mL) and stirred for 20 hr. The solid was filtered, and washed with dichloromethane (500 mL). The reaction was performed twice under similar conditions, and dichloromethane (400 mL) was added to the obtained 3 batches of solid. The mixture was filtered, washed twice with dichloromethane (100 mL) and dried at 50° C. to give a yellow solid (139 g). Toluene (1390 mL) was added to the solid, and the mixture was heated to 60° C., ethanol (1250 mL) was slowly added, and the mixture was stirred at 80° C. for 1 hr. After cooling to room temperature, the solid was filtered, washed twice with toluene/ethanol (9/1, 200 mL), twice with toluene (200 mL), and 4 times with hexane (300 mL), and dried at 50° C. to give the object sodium[(4-tert-butylphenyl)sulfonyl][4-chloro-2-(1-oxidoisonicotinoyl)phenyl]azanide (128 g, yellow solid). [0126] MS: [M+H]+445.1. [0127] 1H NMR (400 MHz, DMSO-d6) δ 1.27 (9H, s), 6.96 (1H, s), 7.00-7.12 (1H, m), 7.25 (1H, d, J=8.9 Hz), 7.93 (6H, m), 8.15 (2H, d, J=6.8 Hz). [0128] Anal. Calcd for C22H20ClN2O4SNa: C, 56.59; H, 4.32; N, 6.00; S, 6.87; C1, 7.59. Found: C, 56.20; H, 4.29; N, 5.95; S, 6.50; Cl, 7.64. |
| 258.3 g |
With sodium hydroxide In water at 25 - 78℃; for 0.833333h; |
1 An Anhydrous Crystalline Sodium Salt of 4-tert- butyl-N-[4-chloro-2-(i -oxy-pyridine-4-carbonyl)-phenyl] -benzenesulfonamide
A reaction vessel was charged with 300 g 4-tert-butyl-N- [4-chloro-2-(i -oxy-pyridine-4-carbonyl)-phenyl]-benzene- sulfonamide, 4,737 mE Industrial Methylated Spirits (IMS),and 302.4 mE watet 27.245 g sodium hydroxide pellets were added to the slurry at 25°C. The reaction mixture was agitatedambient temperature for 50 minutes, followed by heating to 78° C. to dissolve all solids. The clear solution was then filtered while maintaining the temperature above 55° C.throughout the filtration process. Afier filtration, the filtered solution was reheated to 75° C. and then cooled to 55° C. and seeded with 3.0 g Compound B-anhydrous crystalline form (prepared by an analogous procedure) as a slurry in iS mE IMS at ambient temperature. The slurry was held at 55° C.overnight and then cooled to 45° C. Vacuum distillation was employed while heating the reactor jacket to 65° C. and not allowing the slurry temperature to exceed 55° C., leaving,500 mE of slurry in the reactot The slurry was cooled to-iO° C., held at that temperature overnight, and then trans40 ferred to a filter dryer and settled for i 0 minutes. The jackettemperature of the filter was pre-chilled to -iO° C. The mother liquors were removed to break-through using 0.5 to i bar nitrogen pressure. The crystallizer was charged with a first pre-chilled wash of i,200 mE IMS, chilled to -iO° C. Thewash was transferred to the cake in the filter, agitated for iO minutes, settled for iO minutes, and removed under 0.5 to i bar nitrogen pressure. The washing of the filter cake was repeated two additional times under the same conditions. The jacket temperature ofthe filterwas increased to 20°C. andthecake was blown-down under 0.5 to i bar nitrogen pressure until the solvent being removed was reduced to a trickle. The wet cake was dried at 70° C. with agitation under vacuum to provide 258.3 g of the title compound as a yellow crystalline solid. |
| 258.3 g |
With sodium hydroxide In ethanol; water at 25℃; |
1 An anhydrous crystalline sodium salt of 4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
A reaction vessel was charged with 300 g 4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide, 4,737 mL Industrial Methylated Spirits (IMS), and 302.4 mL water. 27.245 g sodium hydroxide pellets were added to the slurry at 25° C. The reaction mixture was agitated at ambient temperature for 50 minutes, followed by heating to ˜78° C. to dissolve all solids. The clear solution was then filtered while maintaining the temperature above 55° C. throughout the filtration process. After filtration, the filtered solution was reheated to 75° C. and then cooled to 55° C. and seeded with 3.0 g Compound B-anhydrous crystalline form (prepared by an analogous procedure) as a slurry in 15 mL IMS at ambient temperature. The slurry was held at 55° C. overnight and then cooled to 45° C. Vacuum distillation was employed while heating the reactor jacket to 65° C. and not allowing the slurry temperature to exceed 55° C., leaving ˜1,500 mL of slurry in the reactor. The slurry was cooled to -10° C., held at that temperature overnight, and then transferred to a filter dryer and settled for 10 minutes. The jacket temperature of the filter was pre-chilled to -10° C. The mother liquors were removed to break-through using 0.5 to 1 bar nitrogen pressure. The crystallizer was charged with a first pre-chilled wash of 1,200 mL IMS, chilled to -10° C. The wash was transferred to the cake in the filter, agitated for 10 minutes, settled for 10 minutes, and removed under 0.5 to 1 bar nitrogen pressure. The washing of the filter cake was repeated two additional times under the same conditions. The jacket temperature of the filter was increased to 20° C. and the cake was blown-down under 0.5 to 1 bar nitrogen pressure until the solvent being removed was reduced to a trickle. The wet cake was dried at 70° C. with agitation under vacuum to provide 258.3 g of the title compound as a yellow crystalline solid. |
| 258.3 g |
With sodium hydroxide In water at 20 - 25℃; for 0.833333h; |
1 Preparation of An Anhydrous Crystalline Sodium Salt of 4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
A reaction vessel was charged with 300 g 4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide, 4,737 mL Industrial Methylated Spirits (IMS), and 302.4 mL water. 27.245 g sodium hydroxide pellets were added to the slurry at 25° C. The reaction mixture was agitated at ambient temperature for 50 minutes, followed by heating to 78° C. to dissolve all solids. The clear solution was then filtered while maintaining the temperature above 55° C. throughout the filtration process. After filtration, the filtered solution was reheated to 75° C. and then cooled to 55° C. and seeded with 3.0 g Compound B-anhydrous crystalline form (prepared by an analogous procedure) as a slurry in 15 mL IMS at ambient temperature. The slurry was held at 55° C. overnight and then cooled to 45° C. Vacuum distillation was employed while heating the reactor jacket to 65° C. and not allowing the slurry temperature to exceed 55° C., leaving 1,500 mL of slurry in the reactor. The slurry was cooled to -10° C., held at that temperature overnight, and then transferred to a filter dryer and settled for 10 minutes. The jacket temperature of the filter was pre-chilled to -10° C. The mother liquors were removed to break-through using 0.5 to 1 bar nitrogen pressure. The crystallizer was charged with a first pre-chilled wash of 1,200 mL IMS, chilled to -10° C. The wash was transferred to the cake in the filter, agitated for 10 minutes, settled for 10 minutes, and removed under 0.5 to 1 bar nitrogen pressure. The washing of the filter cake was repeated two additional times under the same conditions. The jacket temperature of the filter was increased to 20° C. and the cake was blown-down under 0.5 to 1 bar nitrogen pressure until the solvent being removed was reduced to a trickle. The wet cake was dried at 70° C. with agitation under vacuum to provide 258.3 g of the title compound as a yellow crystalline solid. |
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