tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate

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

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

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.61 g, 1.22 mmol) in dimethyl sulfoxide (4 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (0.30 g, 1.34 mmol), copper(I) iodide (0.028 g, 0.15 mmol), potassium carbonate (0.41 g, 2.94 mmol), and L-proline (0.034 g, 0.29 mmol). The light yellow reaction mixture was heated to 120° C. After 16 h, the reaction mixture was allowed to cool to room temperature and was diluted with 3 N ammonium hydroxide solution (20 mL). The mixture was extracted with dichloromethane, resulting in a thick emulsion. The emulsion was filtered through Celite to remove any insoluble material. The organic phase was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-5% methanol/dichloromethane elute) afforded 0.53 g (72%) of tert-butyl 2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate. to cool to room temperature The mixture was extracted with dichloromethane resulting in a thick emulsion The emulsion was filtered through Celite to remove any insoluble material The organic phase was washed with water, brine dried over magnesium sulfate filtered concentrated Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-5% methanol/dichloromethane elute)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.61 g, 1.22 mmol) in dimethyl sulfoxide (4 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (0.30 g, 1.34 mmol), copper(I) iodide (0.028 g, 0.15 mmol), potassium carbonate (0.41 g, 2.94 mmol), and L-proline (0.034 g, 0.29 mmol). The light yellow reaction mixture was heated to 120° C. After 16 h, the reaction mixture was allowed to cool to room temperature and was diluted with 3 N ammonium hydroxide solution (20 mL). The mixture was extracted with dichloromethane, resulting in a thick emulsion. The emulsion was filtered through Celite to remove any insoluble material. The organic phase was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-5% methanol/dichloromethane elute) afforded 0.53 g (72%) of tert-butyl 2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate. to cool to room temperature The mixture was extracted with dichloromethane resulting in a thick emulsion The emulsion was filtered through Celite to remove any insoluble material The organic phase was washed with water, brine dried over magnesium sulfate filtered concentrated Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-5% methanol/dichloromethane elute)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of 2,5-dibromo-1,3,4-thiadiazole (245 mg, 1.004 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (290 mg, 1.105 mmol) and DIPEA (702 μL, 1.02 mmol) in dioxane (2.5 mL) was heated at 120° C. for 1 hour. The reaction mixture was diluted with water (10 mL), extracted with DCM (20 mL), and the organic phase was concentrated onto silica gel. The crude material was purified by flash chromatography using a 24 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a yellow oil (343 mg, 88% yield). LC-MS: Rt 1.25 min; MS m/z 391.2 [M+2]+ [Method A]. 1H NMR (400 MHz, Chloroform-d) δ 3.87 (s, 4H), 3.34-3.43 (m, 4H), 1.73-1.85 (m, 4H), 1.46 (s, 9H). extracted with DCM (20 mL) the organic phase was concentrated onto silica gel The crude material was purified by flash chromatography

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of 2,5-dibromo-1,3,4-thiadiazole (245 mg, 1.004 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (290 mg, 1.105 mmol) and DIPEA (702 μL, 1.02 mmol) in dioxane (2.5 mL) was heated at 120° C. for 1 hour. The reaction mixture was diluted with water (10 mL), extracted with DCM (20 mL), and the organic phase was concentrated onto silica gel. The crude material was purified by flash chromatography using a 24 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a yellow oil (343 mg, 88% yield). LC-MS: Rt 1.25 min; MS m/z 391.2 [M+2]+ [Method A]. 1H NMR (400 MHz, Chloroform-d) δ 3.87 (s, 4H), 3.34-3.43 (m, 4H), 1.73-1.85 (m, 4H), 1.46 (s, 9H). extracted with DCM (20 mL) the organic phase was concentrated onto silica gel The crude material was purified by flash chromatography

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

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

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.61 g, 1.22 mmol) in dimethyl sulfoxide (4 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (0.30 g, 1.34 mmol), copper(I) iodide (0.028 g, 0.15 mmol), potassium carbonate (0.41 g, 2.94 mmol), and L-proline (0.034 g, 0.29 mmol). The light yellow reaction mixture was heated to 120° C. After 16 h, the reaction mixture was allowed to cool to room temperature and was diluted with 3 N ammonium hydroxide solution (20 mL). The mixture was extracted with dichloromethane, resulting in a thick emulsion. The elmusion was filtered through Celite to remove any insoluble material. The organic phase was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-5% methanol/dichloromethane elute) afforded 0.53 g (72%) of tert-butyl 2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate. to cool to room temperature The mixture was extracted with dichloromethane resulting in a thick emulsion The elmusion was filtered through Celite to remove any insoluble material The organic phase was washed with water, brine dried over magnesium sulfate filtered concentrated Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-5% methanol/dichloromethane elute)

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

Procedure: 2-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester was prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 2,7-diaza-spiro[3.5]-nonane-7-carboxylic acid tert-butyl ester in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. 2-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester was subsequently BOC-deprotected to give the title compound as a pale yellow oil (287 mg, 58%).