4-bromobut-1-yne

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

Procedure: Sodium hydride (60% dispersion in mineral oil, 3.9 g, 17.2 mmol, 1.2 equiv) was added to a solution of ethyl 2-(methylsulfonyl)propanoate (14.8 g, 82.0 mmol, 1.0 equiv) in N,N-dimethylformamide (180 mL) at room temperature. After the evolution of gas subsided (approx. 30 min), a stirred mixture of potassium iodide (2.89 g, 17.2 mmol, 0.2 equiv) and 4-bromobut-1-yne (10.9 g, 82.0 mmol, 1.0 equiv) in N,N-dimethylformamide (20 mL) was added dropwise via cannula (approx. 2 h). After 3 h, the reaction was quenched with water (200 mL), and the resulting solution was extracted with 1:1 ethyl acetate-hexanes (2×200 mL). The combined organic phases were washed with water (2×50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (340 g silica gel column, 0-25% gradient ethyl acetate in hexanes) to provide the title compound as a clear colorless oil (6.63 g, 35%). MS (GCMS) m/z 233 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ1.33 (t, J=7.12 Hz, 3H) 1.64 (s, 3H) 2.00 (t, J=2.63 Hz, 1H) 2.11-2.22 (m, 1H) 2.22-2.32 (m, 1H) 2.33-2.45 (m, 1H) 2.46-2.58 (m, 1H) 3.05 (s, 3H) 4.28 (q, J=7.16 Hz, 2H). (approx. 30 min) was added dropwise via cannula (approx. 2 h) the reaction was quenched with water (200 mL) the resulting solution was extracted with 1:1 ethyl acetate-hexanes (2×200 mL) The combined organic phases were washed with water (2×50 mL), brine (50 mL) dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The crude material was purified by flash chromatography (340 g silica gel column, 0-25% gradient ethyl acetate in hexanes)

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

Procedure: Cesium carbonate (46.66 g, 143.21 mmol) is added to a suspension of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (16.66 g, 57.28 mmoles) in acetonitrile (167 mL). The mixture is stirred for 10 minutes at ambient temperature then 4-bromobutyne (6.45 mL, 68.74 mmol) is added. The reaction is heated to reflux and stirred for 18 hours. The mixture is cooled and concentrated under reduced pressure. The residue is partitioned between water (200 mL) and ethyl acetate (150 mL). The phases are separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layers are washed with water (200 mL), then brine (150 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (17.2 g, 98% yield). 1H NMR (300.11 MHz, CDCl3): δ 3.43-3.31 (m, 4H), 2.53-2.48 (m, 2H), 2.37-2.29 (m, 4H), 2.20 (s, 2H), 1.94 (t, J=2.6 Hz, 1H), 1.44 (s, 17H). The reaction is heated to reflux stirred for 18 hours The mixture is cooled concentrated under reduced pressure The residue is partitioned between water (200 mL) and ethyl acetate (150 mL) The phases are separated the aqueous layer is extracted with ethyl acetate (100 mL) The combined organic layers are washed with water (200 mL) brine (150 mL), dried over MgSO4 filtered concentrated under reduced pressure

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-Boc-piperazine (0.5 g, 2.68 mmol) in acetonitrile (2.5 mL) was added K2CO3 (0.55 g, 4.02 mmol) followed by 4-bromo-1-butyne (0.39 g, 2.95 mmol). The mixture was heated at 60° C. for 6 h, allowed to come to room temperature, diluted with water and extracted with EtOAc (2×15 mL). The combined organic layers washed with water, brine, dried over Na2SO4 and concentrated under vacuo to afford the title compound (0.55 g, 86%); LCMS: m/z=239.10 (M+1). Method 2minLowp. to come to room temperature extracted with EtOAc (2×15 mL) The combined organic layers washed with water, brine dried over Na2SO4 concentrated under vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-Boc-piperazine (0.5 g, 2.68 mmol) in acetonitrile (2.5 mL) was added K2CO3 (0.55 g, 4.02 mmol) followed by 4-bromo-1-butyne (0.39 g, 2.95 mmol). The mixture was heated at 60° C. for 6 h, allowed to come to room temperature, diluted with water and extracted with EtOAc (2×15 mL). The combined organic layers washed with water, brine, dried over Na2SO4 and concentrated under vacuo to afford the title compound (0.55 g, 86%); LCMS: m/z=239.10 (M+1). Method 2minLowp. to come to room temperature extracted with EtOAc (2×15 mL) The combined organic layers washed with water, brine dried over Na2SO4 concentrated under vacuo

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

Procedure: Sodium hydride (60% dispersion in mineral oil, 3.9 g, 17.2 mmol, 1.2 equiv) was added to a solution of ethyl 2-(methylsulfonyl)propanoate (14.8 g, 82.0 mmol, 1.0 equiv) in N,N-dimethylformamide (180 mL) at room temperature. After the evolution of gas subsided (approx. 30 min), a stirred mixture of potassium iodide (2.89 g, 17.2 mmol, 0.2 equiv) and 4-bromobut-1-yne (10.9 g, 82.0 mmol, 1.0 equiv) in N,N-dimethylformamide (20 mL) was added dropwise via cannula (approx. 2 h). After 3 h, the reaction was quenched with water (200 mL), and the resulting solution was extracted with 1:1 ethyl acetate-hexanes (2×200 mL). The combined organic phases were washed with water (2×50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (340 g silica gel column, 0-25% gradient ethyl acetate in hexanes) to provide the title compound as a clear colorless oil (6.63 g, 35%). MS (GCMS) m/z 233 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ1.33 (t, J=7.12 Hz, 3H) 1.64 (s, 3H) 2.00 (t, J=2.63 Hz, 1H) 2.11-2.22 (m, 1H) 2.22-2.32 (m, 1H) 2.33-2.45 (m, 1H) 2.46-2.58 (m, 1H) 3.05 (s, 3H) 4.28 (q, J=7.16 Hz, 2H). (approx. 30 min) was added dropwise via cannula (approx. 2 h) the reaction was quenched with water (200 mL) the resulting solution was extracted with 1:1 ethyl acetate-hexanes (2×200 mL) The combined organic phases were washed with water (2×50 mL), brine (50 mL) dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The crude material was purified by flash chromatography (340 g silica gel column, 0-25% gradient ethyl acetate in hexanes)

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

Procedure: Cesium carbonate (46.66 g, 143.21 mmol) is added to a suspension of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (16.66 g, 57.28 mmoles) in acetonitrile (167 mL). The mixture is stirred for 10 minutes at ambient temperature then 4-bromobutyne (6.45 mL, 68.74 mmol) is added. The reaction is heated to reflux and stirred for 18 hours. The mixture is cooled and concentrated under reduced pressure. The residue is partitioned between water (200 mL) and ethyl acetate (150 mL). The phases are separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layers are washed with water (200 mL), then brine (150 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (17.2 g, 98% yield). 1H NMR (300.11 MHz, CDCl3): δ 3.43-3.31 (m, 4H), 2.53-2.48 (m, 2H), 2.37-2.29 (m, 4H), 2.20 (s, 2H), 1.94 (t, J=2.6 Hz, 1H), 1.44 (s, 17H). The reaction is heated to reflux stirred for 18 hours The mixture is cooled concentrated under reduced pressure The residue is partitioned between water (200 mL) and ethyl acetate (150 mL) The phases are separated the aqueous layer is extracted with ethyl acetate (100 mL) The combined organic layers are washed with water (200 mL) brine (150 mL), dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: Cesium carbonate (46.66 g, 143.21 mmol) is added to a suspension of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (16.66 g, 57.28 mmoles) in acetonitrile (167 mL). The mixture is stirred for 10 minutes at ambient temperature then 4-bromobutyne (6.45 mL, 68.74 mmol) is added. The reaction is heated to reflux and stirred for 18 hours. The mixture is cooled and concentrated under reduced pressure. The residue is partitioned between water (200 mL) and ethyl acetate (150 mL). The phases are separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layers are washed with water (200 mL), then brine (150 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (17.2 g, 98% yield). 1H NMR (300.11 MHz, CDCl3): δ 3.43-3.31 (m, 4H), 2.53-2.48 (m, 2H), 2.37-2.29 (m, 4H), 2.20 (s, 2H), 1.94 (t, J=2.6 Hz, 1H), 1.44 (s, 17H). The reaction is heated to reflux stirred for 18 hours The mixture is cooled concentrated under reduced pressure The residue is partitioned between water (200 mL) and ethyl acetate (150 mL) The phases are separated the aqueous layer is extracted with ethyl acetate (100 mL) The combined organic layers are washed with water (200 mL) brine (150 mL), dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: Add tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (46.07 mmol) and cesium carbonate (115.2 mmol) to a solution of acetonitrile (200 mL). After stirring at room temperature for 20 minutes, add 4-bromobutyne (69.1 mmol) and heat the mixture to reflux with stirring overnight. Cool to room temperature and dilute with ethyl acetate (200 mL). Filter the reaction through a glass frit rinsing with ethyl acetate (2×100 mL). Concentrate the crude mixture under reduced pressure, then add ethyl acetate (200 mL) and wash the organics with water (200 mL) and brine (200 mL). Dry the organics over sodium sulfate, filter, and concentrate under reduced pressure to yield crude tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate (13.6 g, 44.4 mmol): MS (m/z): 307.2 (M+H). To a round bottom flask under nitrogen, add tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate (44.4 mmol), triethylamine (4.44 mmol), zirconocene chloride (4.44 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (48.8 mmol). Heat this mixture to 60° C. for 3 hours, then stir overnight at room temperature. Dissolve the mixture in dichloromethane (20 mL) and purify by flash chromatography (330 g silica gel cartridge) eluting with 15-85% ethyl acetate in hexanes to yield the final title compound, tert-butyl 4-[(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate (29.9 mmol) as a light yellow oil: MS (m/z): 435.2 (M+H). heat the mixture to reflux with stirring overnight Cool to room temperature Filter the reaction through a glass frit rinsing with ethyl acetate (2×100 mL) Concentrate the crude mixture under reduced pressure add ethyl acetate (200 mL) and wash the organics with water (200 mL) and brine (200 mL) Dry the organics over sodium sulfate filter concentrate under reduced pressure to yield crude tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate (13.6 g, 44.4 mmol) Heat this mixture to 60° C. for 3 hours stir overnight at room temperature purify by flash chromatography (330 g silica gel cartridge) eluting with 15-85% ethyl acetate in hexanes

Conditions: temp:67.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Charge in order, 23.7 g of CH3CN, 10 g of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate, 9.2 g of K2CO3 then 8.4 g of 4-bromobut-1-yne to R1. Heat the mixture to 65-70° C. and stir the mixture at 65-70° C. for 12-18 hours. Concentrate the mixture to a total weight of 30-40 g below 50° C., then add 76 g of MTBE and 50 g of water. Stir the mixture at 20-25° C. for 30 mins then allow to stand to 30 mins Separate the aqueous. Preopare a solution of 1 g of KOH in 49 g of water and add this to the organic layer at 20-25° C. Stir the mixture at 20-25° C. for 30 mins then allow to stand for 20-30 mins at 20-25° C. Separate the aqueous layer out and wash the organics with 50 g of water. Concentrate the organic phase to 40-50 g total weight below 50° C. in R1. Prepare a solution of 7.4 g of oxalic acid dihydrate in 39.5 g of acetone, then add drop wise the oxalic acid/acetone solution into R1 at 20-25° C. Stir the suspension at 20-25° C. for 2-3 hours then filter. Wash the cake with 15.2 g of MTBE. Slurry the cake in 89 g of THF and stir the mixture at 50° C. for 6-8 hours. Cool the mixture to 20-25° C. and filter. Wash the cake with 17.8 g of THF. Again, slurry the cake in 89 g of THF and stir the mixture at 50° C. for 6-8 hours. Cool the mixture to 20-25° C. and filter. Wash the cake with 17.8 g of THF. Dry the cake under vacuum at 50-60° C. for 16-18 hours to provide the title compound, tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate; oxalic acid. Concentrate the mixture to a total weight of 30-40 g below 50° C. add 76 g of MTBE and 50 g of water Stir the mixture at 20-25° C. for 30 mins to stand to 30 mins Separate the aqueous Preopare a solution of 1 g of KOH in 49 g of water and add this to the organic layer at 20-25° C Stir the mixture at 20-25° C. for 30 mins to stand for 20-30 mins at 20-25° C Separate the aqueous layer out and wash the organics with 50 g of water Concentrate the organic phase to 40-50 g total weight below 50° C. in R1 Prepare a solution of 7.4 g of oxalic acid dihydrate in 39.5 g of acetone Stir the suspension at 20-25° C. for 2-3 hours then filter Wash the cake with 15.2 g of MTBE stir the mixture at 50° C. for 6-8 hours Cool the mixture to 20-25° C. filter Wash the cake with 17.8 g of THF stir the mixture at 50° C. for 6-8 hours Cool the mixture to 20-25° C. filter Wash the cake with 17.8 g of THF Dry the cake under vacuum at 50-60° C. for 16-18 hours

Conditions: temp:67.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Charge in order, 23.7 g of CH3CN, 10 g of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate, 9.2 g of K2CO3 then 8.4 g of 4-bromobut-1-yne to R1. Heat the mixture to 65-70° C. and stir the mixture at 65-70° C. for 12-18 hours. Concentrate the mixture to a total weight of 30-40 g below 50° C., then add 76 g of MTBE and 50 g of water. Stir the mixture at 20-25° C. for 30 mins then allow to stand to 30 mins Separate the aqueous. Preopare a solution of 1 g of KOH in 49 g of water and add this to the organic layer at 20-25° C. Stir the mixture at 20-25° C. for 30 mins then allow to stand for 20-30 mins at 20-25° C. Separate the aqueous layer out and wash the organics with 50 g of water. Concentrate the organic phase to 40-50 g total weight below 50° C. in R1. Prepare a solution of 7.4 g of oxalic acid dihydrate in 39.5 g of acetone, then add drop wise the oxalic acid/acetone solution into R1 at 20-25° C. Stir the suspension at 20-25° C. for 2-3 hours then filter. Wash the cake with 15.2 g of MTBE. Slurry the cake in 89 g of THF and stir the mixture at 50° C. for 6-8 hours. Cool the mixture to 20-25° C. and filter. Wash the cake with 17.8 g of THF. Again, slurry the cake in 89 g of THF and stir the mixture at 50° C. for 6-8 hours. Cool the mixture to 20-25° C. and filter. Wash the cake with 17.8 g of THF. Dry the cake under vacuum at 50-60° C. for 16-18 hours to provide the title compound, tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate; oxalic acid. Concentrate the mixture to a total weight of 30-40 g below 50° C. add 76 g of MTBE and 50 g of water Stir the mixture at 20-25° C. for 30 mins to stand to 30 mins Separate the aqueous Preopare a solution of 1 g of KOH in 49 g of water and add this to the organic layer at 20-25° C Stir the mixture at 20-25° C. for 30 mins to stand for 20-30 mins at 20-25° C Separate the aqueous layer out and wash the organics with 50 g of water Concentrate the organic phase to 40-50 g total weight below 50° C. in R1 Prepare a solution of 7.4 g of oxalic acid dihydrate in 39.5 g of acetone Stir the suspension at 20-25° C. for 2-3 hours then filter Wash the cake with 15.2 g of MTBE stir the mixture at 50° C. for 6-8 hours Cool the mixture to 20-25° C. filter Wash the cake with 17.8 g of THF stir the mixture at 50° C. for 6-8 hours Cool the mixture to 20-25° C. filter Wash the cake with 17.8 g of THF Dry the cake under vacuum at 50-60° C. for 16-18 hours

Conditions: temp:67.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Charge in order, 23.7 g of CH3CN, 10 g of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate, 9.2 g of K2CO3 then 8.4 g of 4-bromobut-1-yne to R1. Heat the mixture to 65-70° C. and stir the mixture at 65-70° C. for 12-18 hours. Concentrate the mixture to a total weight of 30-40 g below 50° C., then add 76 g of MTBE and 50 g of water. Stir the mixture at 20-25° C. for 30 mins then allow to stand to 30 mins Separate the aqueous. Preopare a solution of 1 g of KOH in 49 g of water and add this to the organic layer at 20-25° C. Stir the mixture at 20-25° C. for 30 mins then allow to stand for 20-30 mins at 20-25° C. Separate the aqueous layer out and wash the organics with 50 g of water. Concentrate the organic phase to 40-50 g total weight below 50° C. in R1. Prepare a solution of 7.4 g of oxalic acid dihydrate in 39.5 g of acetone, then add drop wise the oxalic acid/acetone solution into R1 at 20-25° C. Stir the suspension at 20-25° C. for 2-3 hours then filter. Wash the cake with 15.2 g of MTBE. Slurry the cake in 89 g of THF and stir the mixture at 50° C. for 6-8 hours. Cool the mixture to 20-25° C. and filter. Wash the cake with 17.8 g of THF. Again, slurry the cake in 89 g of THF and stir the mixture at 50° C. for 6-8 hours. Cool the mixture to 20-25° C. and filter. Wash the cake with 17.8 g of THF. Dry the cake under vacuum at 50-60° C. for 16-18 hours to provide the title compound, tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate; oxalic acid. Concentrate the mixture to a total weight of 30-40 g below 50° C. add 76 g of MTBE and 50 g of water Stir the mixture at 20-25° C. for 30 mins to stand to 30 mins Separate the aqueous Preopare a solution of 1 g of KOH in 49 g of water and add this to the organic layer at 20-25° C Stir the mixture at 20-25° C. for 30 mins to stand for 20-30 mins at 20-25° C Separate the aqueous layer out and wash the organics with 50 g of water Concentrate the organic phase to 40-50 g total weight below 50° C. in R1 Prepare a solution of 7.4 g of oxalic acid dihydrate in 39.5 g of acetone Stir the suspension at 20-25° C. for 2-3 hours then filter Wash the cake with 15.2 g of MTBE stir the mixture at 50° C. for 6-8 hours Cool the mixture to 20-25° C. filter Wash the cake with 17.8 g of THF stir the mixture at 50° C. for 6-8 hours Cool the mixture to 20-25° C. filter Wash the cake with 17.8 g of THF Dry the cake under vacuum at 50-60° C. for 16-18 hours

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-1-butyne (0.500 g, 3.76 mmol) in acetonitrile (20 mL) was added with 1-tert-butoxycarbonylpiperazine (0.700 g, 3.76 mmol) and potassium carbonate (0.779 g, 5.64 mmol), and the mixture was stirred at 60° C. for 6 hours. The reaction mixture was added with water, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-(but-3-ynyl)piperazine-1-carboxylate (0.621 g, 69%). the mixture was extracted with methylene chloride The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate)