N-[3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide

Step C: A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 , 1 -dimethylethyl)-1 , 3-thiazol-4-yl]-2- fluorophenyl}-2, 6-difluorobenzenesulfonamide To a reactor vessel was charged /V-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}- 2, 6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ~10°C and N-bromosuccinimide (NBS) (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20°C and stirred for 45 min . Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ~10°C. 2, 2- Dimethylpropanethioamide (1 .3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 °C. After 45 min, the vessel contents were heated to 75°C and held for 1 .75 hours . The reaction mixture was then cooled to 5°C and water (270 ml) was slowly charged keeping the temperature below 30°C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25°C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50°C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0°C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30°C to obtain /V-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 , 1 -dimethylethyl)-1 , 3-thiazol-4-yl]-2- fluorophenyl}-2, 6-difluorobenzenesulfonannide (28.8 g, 80percent).To a reactor vessel was charged N- {3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyl}-2, 6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ~10°C and N-bromosuccinimide (NBS) (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20°C and stirred for 45 min . Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ~10°C. 2, 2-Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 °C. After 45 min, the vessel contents were heated to 75°C and held for 1.75 hours . The reaction mixture was then cooled to 5°C and water (270 ml) was slowly charged keeping the temperature below 30°C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25°C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50°C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0°C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30°C to obtain N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(l, l-dimethylethyl)-l, 3- thiazol-4-yl]-2-fluorophenyl}-2, 6-difluorobenzenesulfonamide (28.8 g, 80percent).Step C: N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(l, l-dimethylethyl)-l, 3-thiazol-4-yl]- 2-fluorophenyl}-2, 6-difluorobenzenesulfonamide To a reactor vessel was charged N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyl}-2, 6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ~10°C and N-bromosuccinimide (NBS) (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20°C and stirred for 45 min . Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ~10°C. 2, 2-Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 °C. After 45 min, the vessel contents were heated to 75°C and held for 1.75 hours . The reaction mixture was then cooled to 5°C and water (270 ml) was slowly charged keeping the temperature below 30°C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25°C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50°C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0°C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30°C to obtain N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(l, l-dimethylethyl)-l, 3- thiazol-4-yl]-2-fluorophenyl}-2, 6-difluorobenzenesulfonamide (28.8 g, 80percent).Ste C: N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(l, l-dimethylethyl)-l, 3-thiazol-4-yl]-2- fluorophenyl}-2, 6-difluorobenzenesulfonamide: To a reactor vessel was charged N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}- 2, 6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ~10°C and N-bromosuccinimide (NBS) (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20°C and stirred for 45 min . Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ~10°C. 2, 2- Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 °C. After 45 min, the vessel contents were heated to 75°C and held for 1.75 hours. The reaction mixture was then cooled to 5°C and water (270 ml) was slowly charged keeping the temperature below 30°C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25 °C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50 °C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0 °C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30°C to obtain N- {3-[5-(2-chloro-4-pyrimidinyl)- 2-(l, l-dimethylethyl)-l, 3-thiazol-4-yl]-2-fluorophenyl}-2, 6-difluorobenzenesulfonamide (28.8 g, 80percent).Intermediate 18: N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1, 1-dimethylethyl)-1, 3-thiazol-4-yl]-2-fluorophenyl}-2, 6-difluorobenzenesulfonamide; To a solution of N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2, 6-difluorobenzenesulfonamide (2.0 g, 4.53 mmol) in 40 mL DMA, 1.0 eq. NBS (0.806 g, 4.53 mmol) was added and the solution was allowed to stir 15 min at rt. 2, 2-dimethylpropanethioamide (0.531 g, 4.53 mmol) was then added at rt. The reaction was heated to 60° C. for 2 hours. The reaction was not complete by LC-MS. The reaction mixture was then heated to 80° C. for an additional hour. The reaction mixture was diluted with water and extracted.x.2 with EtOAc. The combined EtOAc washings were washed with water.x.3 to remove DMA, dried over MgSON-Bromosuccinimide (80mg, 0.45mmol) was added to a solution of /V-(3-(2-(2- chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2, 6-difluorobenzenesulfonamide (0253) (200. Omg, 0.45mmol) in dimethylacetamide (2mL). The reaction mixture was stirred at room temperature for lh then 2, 2, 2-Trimethylthioacetamide (58mg, 0.49mmol) was added. After stirring at room temperature for lh, the medium was stirred at 60°C. Once the reaction was complete, the medium was partitioned between water and EtOAC. The aqueous layer was extracted with EtOAc. Combined organics were washed with water and brine, dried over sodium sulphate, filtered and concentrated under vacuum. Purification by column chromatography on silica gel (cHex/EtOAc, 1/0 to 0/1) afforded the title compound (135mg, 55percent). LC/MS (ESN-{3-[(2-chloro-4-pyrimidinyl) acetyl] -2-fluorophenyl} -2, 6-difluorobenzenesulfonamide (100 g) was added to dichloromethane (1000 ml) and the reaction mixture was cooled to 0-10 °C. To this, N-bromosuccinimide (40.3 g) was added in 3 equal portions. After the addition of N-bromosuccinimide, the reaction mixture was heated to 20 °C and stirred for 1-3 hours. Water was added to the reaction mixture and the organic and aqueous layers were separated. Dichloromethane was added to the aqueous and the layers were again separated. The combined organic layer was concentrated to a volume of 400 ml. To this, ethyl acetate (700 ml) was added and the reaction mixture was concentrated to a volume of 400 ml. Dimethylacetamide (900 ml) and β-cyclodextrin (100 g) were added to the reaction mixture and cooled to 0-10 °C. To this, 2, 2-dimethylpropanethioamide (26.6 g) was added in 3 equal portions. The reaction mixture was warmed to 20-30 °C and stirred. The reaction was further heated to 70-80 °C and stirred for 1-3 hours. The reaction mixture was cooled to 0-10 °C and water (900 ml) was slowly added at 0- 10 °C. To this, ethyl acetate (400 ml) was added and the pH of reaction mass was adjusted to 6.0-8.0 with aqueous ammonia solution. The reaction mixture was stirred and the layers were separated. Ethyl acetate was added to the aqueous layer and the layers were again separated. The combined organic layers were washed with twice with water. The organic layer was treated with activated charcoal (10 g), filtered, and washed with ethyl acetate (100 ml). The filtrate was then concentrated under vacuum at 30-50 °C. To this, ethyl acetate (400 ml) was added and the reaction mass was heated to 50-60 °C. Heptanes (400 ml) were slowly added to the reaction mixture at 50-60 °C. After addition of heptanes, the reaction mass was heated to reflux then cooled to 0-10 °C and maintained for 2-4 hours at same temperature. The solid was filtered and washed with heptanes (200 ml) and dried under vacuum at 30-60 °C to get formula-Ill (N-{3-[5- (2-chloro-4-pyrimidinyl)-2-(l, l-dimethylethyl)-l, 3-thiazol-4-yl]-2-fluorophenyl}-2, 6- difluorobenzenesulfonamide) (70 g).To a reactor vessel was charged A/-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyl}-2, 6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 ml_). The reaction slurry was cooled to ~10°C and N-bromosuccinimide (NBS) (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ~20°C and stirred for 45 min. Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to -120 ml_. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to -120 ml_. Dimethylacetamide (270 ml_) was then added to the reaction mixture and cooled to ~10°C. 2, 2-Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ~5 minutes between additions. The reaction was warmed to 20-25 °C. After 45 min, the vessel contents were heated to 75°C and held for 1.75 hours . The reaction mixture was then cooled to 5°C and water (270 ml) was slowly charged keeping the temperature below 30°C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25°C. The organic layers were then concentrated under heat and vacuum to 120 ml_. The vessel contents were then heated to 50°C and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0°C and held for ~2 hrs. The solids were filtered and rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30°C to obtain A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (1 , 1-dimethylethyl)-1 , 3-thiazol-4-yl]-2-fluorophenyl}-2, 6-difluorobenzenesulfonamide (28.8 g, 80percent).

Molecular Weight:539.0
XLogP3:6.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:10
Rotatable Bond Count:6
Exact Mass:538.0511804
Monoisotopic Mass:538.0511804
Topological Polar Surface Area:122
Heavy Atom Count:35
Complexity:821
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes