tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaH (308 mg, 7.69 mmol, 60% in mineral oil) was added to an ice-cold solution of tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate [1198284-94-4] (1.127 g, 4.08 mmol), 2-(2-(bromomethyl)phenyl)-2H-1,2,3-triazole (described separately as building block) (1.0 g, 4.16 mmol) and TBAI (78 mg, 0.208 mmol) in THF (30 mL). The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was allowed to warm to rt and stirred for 4 h. To the mixture water was added and the solution was extracted twice with ethyl acetate. The organic layer was washed with water and brine, filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The product was purified by flash-column chromatography over silicagel (eluent: gradient 5%-65% ethyl acetate/heptane) to yield the title compound (1.77 g, 99%). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.11 (s, 2H), 7.61-7.59 (m, 1H), 7.52-7.46 (m, 2H), 7.23 (d, 1H), 4.53 (s, 2H), 3.69-3.65 (m, 2H), 3.11-3.07 (m, 2H), 3.03 (br s, 2H), 1.86-1.72 (m, 6H), 1.45-1.40 (m, 2H), 1.38 (s, 9H); LCMS RtA=1.17, [M+H]+=426.4]. to warm to rt stirred for 4 h the solution was extracted twice with ethyl acetate The organic layer was washed with water and brine filtered dried over anhydrous sodium sulfate The organic layer was concentrated under reduced pressure The product was purified by flash-column chromatography over silicagel (eluent: gradient 5%-65% ethyl acetate/heptane)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (1.238 mL, 8.60 mmol) in THF (40 mL) n-butyllithium (6.01 mL, 9.61 mmol) was added at 0° C. and the mixture was stirred for 30 min at 0° C. Then a solution of tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate [1198284-94-4] (2.57 g, 9.28 mmol) in THF (10 mL) was added within 3 min and the mixture was stirred for 30 min at 0° C. 3-(bromomethyl)-1-tosyl-1H-indole [58550-81-5] (3.2 g, 8.43 mmol) in THF (10 mL) was dropped to the reaction mixture within 15 min. The mixture was stirred at 0° C. for 1 h and allowed to warm to room temperature overnight. The reaction mixture was quenched with ice-cold water and extracted with TBME (2×150 mL). The combined organic layers were washed with 5% aqueous citric acid and brine, dried over anhydrous Na2SO4, filtered and concentrated (5.3 g, 100%). [1H NMR (400 MHz, DMSO-d8) ♀ ppm 7.88 (d, J=8.28 Hz, 1H), 7.81 (d, J=8.28 Hz, 2H), 7.74 (s, 1H), 7.55 (d, J=7.78 Hz, 1H), 7.36 (d, J=8.03 Hz, 2H), 7.32 (t, J=7.91 Hz, 1H), 7.25-7.21 (m, 1H), 4.58 (s, 2H), 3.75-3.63 (m, 2H), 3.09 (t, J=5.77 Hz, 2H), 2.99 (br. s., 2H), 2.30 (s, 3H), 1.90-1.80 (m, 2H), 1.72-1.57 (m, 4H), 1.39 (s, 9H), 1.36-1.28 (m, 2H); LCMS RtA=1.37 min, [M+H]+=552.3]. the mixture was stirred for 30 min at 0° C The mixture was stirred at 0° C. for 1 h to warm to room temperature overnight The reaction mixture was quenched with ice-cold water extracted with TBME (2×150 mL) The combined organic layers were washed with 5% aqueous citric acid and brine dried over anhydrous Na2SO4 filtered concentrated (5.3 g, 100%) [1H NMR (400 MHz, DMSO-d8) ♀ ppm 7.88 (d, J=8.28 Hz, 1H), 7.81 (d, J=8.28 Hz, 2H), 7.74 (s, 1H), 7.55 (d, J=7.78 Hz, 1H), 7.36 (d, J=8.03 Hz, 2H), 7.32 (t, J=7.91 Hz, 1H), 7.25-7.21 (m, 1H), 4.58 (s, 2H), 3.75-3.63 (m, 2H), 3.09 (t, J=5.77 Hz, 2H), 2.99 (br. s., 2H), 2.30 (s, 3H), 1.90-1.80 (m, 2H), 1.72-1.57 (m, 4H), 1.39 (s, 9H), 1.36-1.28 (m, 2H); LCMS RtA=1.37 min, [M+H]+=552.3]

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

Procedure: A solution of tert-butyl 1-Oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylate (400 mg, 1.5 mmol) in DMF (2 ml) was added slowly at rt to a suspension of sodium hydride 95% (54 mg, 2.24 mmol) in THF (6 ml). The reaction mixture was stirred for 20 min at rt. Then a solution of 1-(chloromethyl)naphthalene (0.33 ml, 2.24 mmol) in THF (2 ml) was added dropwise followed by the addition of tetrabutylammonium iodide (55 mg, 0.15 mmol). The mixture was stirred at 45° C. for 18 h. The reaction mixture was quenched with H2O (50 ml) and extracted twice with EtOAc (50 ml). The combined organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (hexane/EtOAc 2:1) to yield 377 mg (61%) of the title compound. [1H NMR (DMSO, 400 MHz) δ 8.01 (m, 1H), 7.93 (m, 1H), 7.85 (m, 1H), 7.55-7.42 (m, 3H), 7.30 (m, 1H), 4.95 (s, 2H), 3.72 (m, 2H), 3.15-2.95 (m, 4H), 1.98-1.82 (m, 2H), 1.78-1.62 (m, 4H), 1.48-1.38 (m, 2H), 1.39 (s, 9H)]. The mixture was stirred at 45° C. for 18 h The reaction mixture was quenched with H2O (50 ml) extracted twice with EtOAc (50 ml) The combined organic layer was dried over Na2SO4 filtered evaporated The residue was purified by flash chromatography (hexane/EtOAc 2:1)

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

Procedure: To the stirred solution of tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (3.0 g, 11.19 mmol) in DCM (60 mL) was added 4N HCl in dioxane (20 mL) and the mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure and triturated with diethyl ether (2×5 mL) to yield the title compound as a solid (2.2 g, 96%). Note: The product is moisture sensitive. [1H-NMR (DMSO-d6, 300 MHz): δ 9.25-8.68 (m, 2H), 7.43 (s, 1H), 7.20-6.25 (m, 2H), 3.61-2.90 (m, 5H), 2.12-1.95 (m, 2H), 1.76-1.49 (m, 5H); LCMS RtA=0.326, [M+H]+=169.0]. The solvent was removed under reduced pressure triturated with diethyl ether (2×5 mL)

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

Procedure: A heterogeneous mixture of Raney Ni (5.0 g) in ethanolic ammonia (˜20% v/v) and 1-tert-butyl 4-ethyl 4-(2-cyanoethyl)piperidine-1,4-dicarboxylate (8.5 g, 27.42 mmol) was hydrogenated at 100 psi for 48 h at rt in an autoclave. After completion of the reaction, the catalyst was filtered off and washed with ethanol. The combined filtrate was concentrated under reduced pressure and triturated with n-pentane to yield a solid which was purified by column chromatography (eluent=6% methanol in chloroform) to furnish the title compound as a white solid (3.0 g, 41%). [1H-NMR (DMSO-d6, 300 MHz): δ 7.38 (s, 1H), 3.68-3.60 (m, 2H), 3.18-2.95 (m, 4H), 1.89-1.58 (m, 4H), 1.45-1.22 (m, 13H); HPLC RtA=3.835 min (96%); LCMS RtA=1.630, [M+H-Boc]+=169.1]. After completion of the reaction the catalyst was filtered off washed with ethanol The combined filtrate was concentrated under reduced pressure triturated with n-pentane to yield a solid which was purified by column chromatography (eluent=6% methanol in chloroform)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaH (308 mg, 7.69 mmol, 60% in mineral oil) was added to an ice-cold solution of tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate [1198284-94-4] (1.127 g, 4.08 mmol), 2-(2-(bromomethyl)phenyl)-2H-1,2,3-triazole (described separately as building block) (1.0 g, 4.16 mmol) and TBAI (78 mg, 0.208 mmol) in THF (30 mL). The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was allowed to warm to rt and stirred for 4 h. To the mixture water was added and the solution was extracted twice with ethyl acetate. The organic layer was washed with water and brine, filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The product was purified by flash-column chromatography over silicagel (eluent: gradient 5%-65% ethyl acetate/heptane) to yield the title compound (1.77 g, 99%). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.11 (s, 2H), 7.61-7.59 (m, 1H), 7.52-7.46 (m, 2H), 7.23 (d, 1H), 4.53 (s, 2H), 3.69-3.65 (m, 2H), 3.11-3.07 (m, 2H), 3.03 (br s, 2H), 1.86-1.72 (m, 6H), 1.45-1.40 (m, 2H), 1.38 (s, 9H); LCMS RtA=1.17, [M+H]+=426.4]. to warm to rt stirred for 4 h the solution was extracted twice with ethyl acetate The organic layer was washed with water and brine filtered dried over anhydrous sodium sulfate The organic layer was concentrated under reduced pressure The product was purified by flash-column chromatography over silicagel (eluent: gradient 5%-65% ethyl acetate/heptane)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (1.238 mL, 8.60 mmol) in THF (40 mL) n-butyllithium (6.01 mL, 9.61 mmol) was added at 0° C. and the mixture was stirred for 30 min at 0° C. Then a solution of tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate [1198284-94-4] (2.57 g, 9.28 mmol) in THF (10 mL) was added within 3 min and the mixture was stirred for 30 min at 0° C. 3-(bromomethyl)-1-tosyl-1H-indole [58550-81-5] (3.2 g, 8.43 mmol) in THF (10 mL) was dropped to the reaction mixture within 15 min. The mixture was stirred at 0° C. for 1 h and allowed to warm to room temperature overnight. The reaction mixture was quenched with ice-cold water and extracted with TBME (2×150 mL). The combined organic layers were washed with 5% aqueous citric acid and brine, dried over anhydrous Na2SO4, filtered and concentrated (5.3 g, 100%). [1H NMR (400 MHz, DMSO-d8) ♀ ppm 7.88 (d, J=8.28 Hz, 1H), 7.81 (d, J=8.28 Hz, 2H), 7.74 (s, 1H), 7.55 (d, J=7.78 Hz, 1H), 7.36 (d, J=8.03 Hz, 2H), 7.32 (t, J=7.91 Hz, 1H), 7.25-7.21 (m, 1H), 4.58 (s, 2H), 3.75-3.63 (m, 2H), 3.09 (t, J=5.77 Hz, 2H), 2.99 (br. s., 2H), 2.30 (s, 3H), 1.90-1.80 (m, 2H), 1.72-1.57 (m, 4H), 1.39 (s, 9H), 1.36-1.28 (m, 2H); LCMS RtA=1.37 min, [M+H]+=552.3]. the mixture was stirred for 30 min at 0° C The mixture was stirred at 0° C. for 1 h to warm to room temperature overnight The reaction mixture was quenched with ice-cold water extracted with TBME (2×150 mL) The combined organic layers were washed with 5% aqueous citric acid and brine dried over anhydrous Na2SO4 filtered concentrated (5.3 g, 100%) [1H NMR (400 MHz, DMSO-d8) ♀ ppm 7.88 (d, J=8.28 Hz, 1H), 7.81 (d, J=8.28 Hz, 2H), 7.74 (s, 1H), 7.55 (d, J=7.78 Hz, 1H), 7.36 (d, J=8.03 Hz, 2H), 7.32 (t, J=7.91 Hz, 1H), 7.25-7.21 (m, 1H), 4.58 (s, 2H), 3.75-3.63 (m, 2H), 3.09 (t, J=5.77 Hz, 2H), 2.99 (br. s., 2H), 2.30 (s, 3H), 1.90-1.80 (m, 2H), 1.72-1.57 (m, 4H), 1.39 (s, 9H), 1.36-1.28 (m, 2H); LCMS RtA=1.37 min, [M+H]+=552.3]

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

Procedure: A solution of tert-butyl 1-Oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylate (400 mg, 1.5 mmol) in DMF (2 ml) was added slowly at rt to a suspension of sodium hydride 95% (54 mg, 2.24 mmol) in THF (6 ml). The reaction mixture was stirred for 20 min at rt. Then a solution of 1-(chloromethyl)naphthalene (0.33 ml, 2.24 mmol) in THF (2 ml) was added dropwise followed by the addition of tetrabutylammonium iodide (55 mg, 0.15 mmol). The mixture was stirred at 45° C. for 18 h. The reaction mixture was quenched with H2O (50 ml) and extracted twice with EtOAc (50 ml). The combined organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (hexane/EtOAc 2:1) to yield 377 mg (61%) of the title compound. [1H NMR (DMSO, 400 MHz) δ 8.01 (m, 1H), 7.93 (m, 1H), 7.85 (m, 1H), 7.55-7.42 (m, 3H), 7.30 (m, 1H), 4.95 (s, 2H), 3.72 (m, 2H), 3.15-2.95 (m, 4H), 1.98-1.82 (m, 2H), 1.78-1.62 (m, 4H), 1.48-1.38 (m, 2H), 1.39 (s, 9H)]. The mixture was stirred at 45° C. for 18 h The reaction mixture was quenched with H2O (50 ml) extracted twice with EtOAc (50 ml) The combined organic layer was dried over Na2SO4 filtered evaporated The residue was purified by flash chromatography (hexane/EtOAc 2:1)

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

Procedure: To the stirred solution of tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (3.0 g, 11.19 mmol) in DCM (60 mL) was added 4N HCl in dioxane (20 mL) and the mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure and triturated with diethyl ether (2×5 mL) to yield the title compound as a solid (2.2 g, 96%). Note: The product is moisture sensitive. [1H-NMR (DMSO-d6, 300 MHz): δ 9.25-8.68 (m, 2H), 7.43 (s, 1H), 7.20-6.25 (m, 2H), 3.61-2.90 (m, 5H), 2.12-1.95 (m, 2H), 1.76-1.49 (m, 5H); LCMS RtA=0.326, [M+H]+=169.0]. The solvent was removed under reduced pressure triturated with diethyl ether (2×5 mL)

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

Procedure: A heterogeneous mixture of Raney Ni (5.0 g) in ethanolic ammonia (˜20% v/v) and 1-tert-butyl 4-ethyl 4-(2-cyanoethyl)piperidine-1,4-dicarboxylate (8.5 g, 27.42 mmol) was hydrogenated at 100 psi for 48 h at rt in an autoclave. After completion of the reaction, the catalyst was filtered off and washed with ethanol. The combined filtrate was concentrated under reduced pressure and triturated with n-pentane to yield a solid which was purified by column chromatography (eluent=6% methanol in chloroform) to furnish the title compound as a white solid (3.0 g, 41%). [1H-NMR (DMSO-d6, 300 MHz): δ 7.38 (s, 1H), 3.68-3.60 (m, 2H), 3.18-2.95 (m, 4H), 1.89-1.58 (m, 4H), 1.45-1.22 (m, 13H); HPLC RtA=3.835 min (96%); LCMS RtA=1.630, [M+H-Boc]+=169.1]. After completion of the reaction the catalyst was filtered off washed with ethanol The combined filtrate was concentrated under reduced pressure triturated with n-pentane to yield a solid which was purified by column chromatography (eluent=6% methanol in chloroform)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A microwave vial was charged with commercially available tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (Shanghai AQ BioPharma Co., Ltd, catalog #ABP3640, 100 mg, 0.373 mmol), 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (110 mg, 0.447 mmol), Pd2(dba)3 (17 mg, 0.019 mmol), Xantphos (32 mg, 0.056 mmol), and cesium carbonate (182 mg, 0.559 mmol). The vial was sealed, degassed, and filled with toluene (1.5 mL). The reaction mixture was heated at 90° C. overnight, and was filtered through CELITE®. The filtrate was evaporated to give the crude product, which was purified by column chromatography (0-10% MeOH/DCM) to afford the title compound. LC/MS: [(M+1-56)]+=309 The vial was sealed degassed filled with toluene (1.5 mL) was filtered through CELITE® The filtrate was evaporated to give the crude product, which was purified by column chromatography (0-10% MeOH/DCM)