Benzyl 4-iodopiperidine-1-carboxylate

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

Procedure: Iodine (17.6 g, 69.2 mmol) was added dropwise as a solution in THF (40 mL) over 1 hour to an ice cold solution of benzyl 4-hydroxypiperidine-1-carboxylate (15.5 g, 65.9 mmol), imidazole (4.71 g, 69.2 mmol), and triphenylphosphine (18.2 g, 69.2 mmol) in THF (40 mL). This resulting red solution was stirred overnight with warming to room temperature, then cooled back to 0° C. before being quenched with 10% aqueous sodium sulfite. The resulting biphasic mixture was separated and the aqueous layer was extracted with ethyl acetate (1×). The combined extracts were dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography (10% EtOAc/hexane) to give benzyl 4-iodopiperidine-1-carboxylate as a colorless oil (9.50 g, 42% yield). cooled back to 0° C. before being quenched with 10% aqueous sodium sulfite The resulting biphasic mixture was separated the aqueous layer was extracted with ethyl acetate (1×) The combined extracts were dried over magnesium sulfate (MgSO4) filtered concentrated in vacuo to give an oil that was purified by silica gel chromatography (10% EtOAc/hexane)

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

Procedure: A premixed mixture of TMSCl and 1,2-dibromoethane (7:5, v/v, 0.80 mL total volume added) was added dropwise over 5 minutes to a suspension of zinc (1.62 g, 24.8 mmol) in DMA (12 mL) under argon atmosphere. The mixture was stirred for 15 minutes before benzyl 4-iodopiperidine-1-carboxylate (7.13 g, 20.67 mmol) was added dropwise over 15 minutes as a solution in DMA (6 mL). This mixture was stirred for an additional 15 min before it was added slowly to a suspension of 2-chloro-3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)quinoxaline (see PREPARATION P2.8; 5.0 g, 13.8 mmol), copper(I) iodide (0.26 g, 1.38 mmol), and Pd(dppf)Cl2 dichloromethane adduct (0.56 g, 0.69 mmol) in DMA (15 mL) under argon. This mixture was stirred at 80° C. for 2 hours, then cooled to room temperature. Ethyl acetate was added and the suspension was filtered through CELITE® to remove insoluble material. The filtrate was diluted with more ethyl acetate and then washed with water (3×), brine(1×), dried (MgSO4), filtered, and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography (0 to 100% EtOAc/hexane gradient) to give benzyl 4-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)quinoxalin-2-yl)piperidine-1-carboxylate as an off-white solid (6.93 g, 92% yield). v/v, 0.80 mL total volume added) This mixture was stirred at 80° C. for 2 hours the suspension was filtered through CELITE® to remove insoluble material The filtrate was diluted with more ethyl acetate washed with water (3×), brine(1×) dried (MgSO4) filtered concentrated in vacuo to give an oil This oil was purified by silica gel chromatography (0 to 100% EtOAc/hexane gradient)

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

Procedure: A premixed mixture of TMSCl and 1,2-dibromoethane (7:5, v/v, 0.80 mL total volume added) was added dropwise over 5 minutes to a suspension of zinc (1.62 g, 24.8 mmol) in DMA (12 mL) under argon atmosphere. The mixture was stirred for 15 minutes before benzyl 4-iodopiperidine-1-carboxylate (7.13 g, 20.67 mmol) was added dropwise over 15 minutes as a solution in DMA (6 mL). This mixture was stirred for an additional 15 min before it was added slowly to a suspension of 2-chloro-3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)quinoxaline (see PREPARATION P2.8; 5.0 g, 13.8 mmol), copper(I) iodide (0.26 g, 1.38 mmol), and Pd(dppf)Cl2 dichloromethane adduct (0.56 g, 0.69 mmol) in DMA (15 mL) under argon. This mixture was stirred at 80° C. for 2 hours, then cooled to room temperature. Ethyl acetate was added and the suspension was filtered through CELITE® to remove insoluble material. The filtrate was diluted with more ethyl acetate and then washed with water (3×), brine(1×), dried (MgSO4), filtered, and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography (0 to 100% EtOAc/hexane gradient) to give benzyl 4-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)quinoxalin-2-yl)piperidine-1-carboxylate as an off-white solid (6.93 g, 92% yield). v/v, 0.80 mL total volume added) This mixture was stirred at 80° C. for 2 hours the suspension was filtered through CELITE® to remove insoluble material The filtrate was diluted with more ethyl acetate washed with water (3×), brine(1×) dried (MgSO4) filtered concentrated in vacuo to give an oil This oil was purified by silica gel chromatography (0 to 100% EtOAc/hexane gradient)

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

Procedure: Iodine (17.6 g, 69.2 mmol) was added dropwise as a solution in THF (40 mL) over 1 hour to an ice cold solution of benzyl 4-hydroxypiperidine-1-carboxylate (15.5 g, 65.9 mmol), imidazole (4.71 g, 69.2 mmol), and triphenylphosphine (18.2 g, 69.2 mmol) in THF (40 mL). This resulting red solution was stirred overnight with warming to room temperature, then cooled back to 0° C. before being quenched with 10% aqueous sodium sulfite. The resulting biphasic mixture was separated and the aqueous layer was extracted with ethyl acetate (1×). The combined extracts were dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography (10% EtOAc/hexane) to give benzyl 4-iodopiperidine-1-carboxylate as a coloreless oil (9.50 g, 42% yield). cooled back to 0° C. before being quenched with 10% aqueous sodium sulfite The resulting biphasic mixture was separated the aqueous layer was extracted with ethyl acetate (1×) The combined extracts were dried over magnesium sulfate (MgSO4) filtered concentrated in vacuo to give an oil that was purified by silica gel chromatography (10% EtOAc/hexane)

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

Procedure: Iodine (17.6 g, 69.2 mmol) was added dropwise as a solution in THF (40 mL) over 1 hour to an ice cold solution of benzyl 4-hydroxypiperidine-1-carboxylate (15.5 g, 65.9 mmol), imidazole (4.71 g, 69.2 mmol), and triphenylphosphine (18.2 g, 69.2 mmol) in THF (40 mL). This resulting red solution was stirred overnight with warming to room temperature, then cooled back to 0° C. before being quenched with 10% aqueous sodium sulfite. The resulting biphasic mixture was separated and the aqueous layer was extracted with ethyl acetate (1×). The combined extracts were dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography (10% EtOAc/hexane) to give benzyl 4-iodopiperidine-1-carboxylate as a coloreless oil (9.50 g, 42% yield). cooled back to 0° C. before being quenched with 10% aqueous sodium sulfite The resulting biphasic mixture was separated the aqueous layer was extracted with ethyl acetate (1×) The combined extracts were dried over magnesium sulfate (MgSO4) filtered concentrated in vacuo to give an oil that was purified by silica gel chromatography (10% EtOAc/hexane)

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

Procedure: Iodine (17.6 g, 69.2 mmol) was added dropwise as a solution in THF (40 mL) over 1 hour to an ice cold solution of benzyl 4-hydroxypiperidine-1-carboxylate (15.5 g, 65.9 mmol), imidazole (4.71 g, 69.2 mmol), and triphenylphosphine (18.2 g, 69.2 mmol) in THF (40 mL). This resulting red solution was stirred overnight with warming to room temperature, then cooled back to 0° C. before being quenched with 10% aqueous sodium sulfite. The resulting biphasic mixture was separated and the aqueous layer was extracted with ethyl acetate (1×). The combined extracts were dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography (10% EtOAc/hexane) to give benzyl 4-iodopiperidine-1-carboxylate as a coloreless oil (9.50 g, 42% yield). cooled back to 0° C. before being quenched with 10% aqueous sodium sulfite The resulting biphasic mixture was separated the aqueous layer was extracted with ethyl acetate (1×) The combined extracts were dried over magnesium sulfate (MgSO4) filtered concentrated in vacuo to give an oil that was purified by silica gel chromatography (10% EtOAc/hexane)

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

Procedure: Iodine (17.6 g, 69.2 mmol) was added dropwise as a solution in THF (40 mL) over 1 hour to an ice cold solution of benzyl 4-hydroxypiperidine-1-carboxylate (15.5 g, 65.9 mmol), imidazole (4.71 g, 69.2 mmol), and triphenylphosphine (18.2 g, 69.2 mmol) in THF (40 mL). This resulting red solution was stirred overnight with warming to room temperature, then cooled back to 0° C. before being quenched with 10% aqueous sodium sulfite. The resulting biphasic mixture was separated and the aqueous layer was extracted with ethyl acetate (1×). The combined extracts were dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography (10% EtOAc/hexane) to give benzyl 4-iodopiperidine-1-carboxylate as a colorless oil (9.50 g, 42% yield). cooled back to 0° C. before being quenched with 10% aqueous sodium sulfite The resulting biphasic mixture was separated the aqueous layer was extracted with ethyl acetate (1×) The combined extracts were dried over magnesium sulfate (MgSO4) filtered concentrated in vacuo to give an oil that was purified by silica gel chromatography (10% EtOAc/hexane)