3-(4-chloro-2-fluorophenoxy)azetidine

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

Procedure: To a solution of 2,4-dichloro-6-methyl-1,3,5-triazine (0.800 g, 4.87 mmol) in isopropanol (15 mL) was added DIPEA (1.3 mL) and 3-(4-chloro-2-fluorophenoxy)azetidine (0.600 g, 2.92 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-6-methyl-1,3,5-triazine (1.0 g) as a solid. Observed mass (M+1): 329. The crude material was taken to next step without further purification. The mixture was concentrated under reduced pressure extracted with EtOAc (2×40 mL) The organic extracts were washed with brine dried over anhydrous sodium sulfate concentrated under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-((4-chloropyridin-2-yl)amino)-N-methylbenzamide (0.300 g, 1.14 mmol) in Isopropanol (4 mL) was added DIPEA (0.3 mL, 1.71 mmol) and 3-(2-fluoro-4-chlorophenoxy)azetidine (0.230 g, 1.14 mmol) [prepared as described in Example AAA] and the reaction mixture was heated at 80° C. for 7 h. The mixture was concentrated under reduced pressure and extracted with EtOAc (2×20 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 3-((4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)pyridin-2-yl)amino)-N-methylbenzamide (0.10 g, 3%) as a solid. Observed mass (M+1): 427.1 The mixture was concentrated under reduced pressure extracted with EtOAc (2×20 mL) The organic extracts were washed with brine dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by silica gel column chromatography

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

Procedure: To a solution of 3-(4-chloro-2-fluorophenoxy) azetidine (3.6 g, 18.0 mmol) in CH3CN (60 mL, 3 mL/mmol) was added Et3N (7.2 mL, 50.0 mmol) and 2, 4-dichloro-1, 3, 5-triazine (3.0 g, 20.0 mmol) and the reaction mixture was stirred at RT for 1 h. Then the reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×50 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography to obtain 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-1,3,5-triazine (0.800 g, 20%) as a solid. Observed mass (M+1): 315.0 Then the reaction mixture was concentrated under reduced pressure extracted with EtOAc (2×50 mL) The organic extracts were washed with brine dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by column chromatography

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

Procedure: To a solution of 3-(4-chloro-2-fluorophenoxy) azetidine (3.6 g, 18.0 mmol) in acetonitrile (60 mL, 3 mL/mmol) was added TEA (7.2 mL, 50.0 mmol) and 2, 4-dichloro-1, 3, 5-triazine (3.0 g, 20.0 mmol) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×50 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-1,3,5-triazine (0.800 g, 20%) as a solid. Observed mass (M+1): 315.0 The reaction mixture was concentrated under reduced pressure extracted with EtOAc (2×50 mL) The organic extracts were washed with brine dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by silica gel column chromatography

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

Procedure: To a solution of 2,4-dichloro-6-methyl-1,3,5-triazine (0.800 g, 4.87 mmol) in isopropanol (15 mL) was added DIPEA (1.3 mL) and 3-(4-chloro-2-fluorophenoxy)azetidine (0.600 g, 2.92 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-6-methyl-1,3,5-triazine (1.0 g) as a solid. Observed mass (M+1): 329. The crude material was taken to next step without further purification. The mixture was concentrated under reduced pressure extracted with EtOAc (2×40 mL) The organic extracts were washed with brine dried over anhydrous sodium sulfate concentrated under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-((4-chloropyridin-2-yl)amino)-N-methylbenzamide (0.300 g, 1.14 mmol) in Isopropanol (4 mL) was added DIPEA (0.3 mL, 1.71 mmol) and 3-(2-fluoro-4-chlorophenoxy)azetidine (0.230 g, 1.14 mmol) [prepared as described in Example AAA] and the reaction mixture was heated at 80° C. for 7 h. The mixture was concentrated under reduced pressure and extracted with EtOAc (2×20 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 3-((4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)pyridin-2-yl)amino)-N-methylbenzamide (0.10 g, 3%) as a solid. Observed mass (M+1): 427.1 The mixture was concentrated under reduced pressure extracted with EtOAc (2×20 mL) The organic extracts were washed with brine dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by silica gel column chromatography

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

Procedure: To a solution of 3-(4-chloro-2-fluorophenoxy) azetidine (3.6 g, 18.0 mmol) in CH3CN (60 mL, 3 mL/mmol) was added Et3N (7.2 mL, 50.0 mmol) and 2, 4-dichloro-1, 3, 5-triazine (3.0 g, 20.0 mmol) and the reaction mixture was stirred at RT for 1 h. Then the reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×50 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography to obtain 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-1,3,5-triazine (0.800 g, 20%) as a solid. Observed mass (M+1): 315.0 Then the reaction mixture was concentrated under reduced pressure extracted with EtOAc (2×50 mL) The organic extracts were washed with brine dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by column chromatography

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

Procedure: To a solution of 3-(4-chloro-2-fluorophenoxy) azetidine (3.6 g, 18.0 mmol) in acetonitrile (60 mL, 3 mL/mmol) was added TEA (7.2 mL, 50.0 mmol) and 2, 4-dichloro-1, 3, 5-triazine (3.0 g, 20.0 mmol) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×50 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-1,3,5-triazine (0.800 g, 20%) as a solid. Observed mass (M+1): 315.0 The reaction mixture was concentrated under reduced pressure extracted with EtOAc (2×50 mL) The organic extracts were washed with brine dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by silica gel column chromatography