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

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

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

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

Procedure: Charge 435 g of toluene then 302.1 g of sodium bis(2-methoxyethoxy)aluminum hydride to R1. Cool the mixture to −5° C.˜5° C. Charge 652.5 g of toluene and 50 g of tert-butyl 4-(3-chloropropyl)-4-cyano-piperidine-1-carboxylate into R2 and stir the mixture until clear. Add the solution of tert-butyl 4-(3-chloropropyl)-4-cyano-piperidine-1-carboxylate in R2 drop-wise to R1, control the temperature below 5° C. Stir the mixture in R1 for 0.5 hour at −5° C.˜5° C. then warm the mixture to 15˜20° C. and stir for 1˜3 hours. Charge 25 g of sodium carbonate to R2 then add 1500 g of water and cool the mixture to 0˜10° C. Add the mixture in R1 drop-wise to R2, controlling the temperature below 10° C. Warm the mixture to 20˜40° C. and stir for 10-20 mins then allow to stand for 40-60 mins Separate the aqueous layer and wash the organic layer with 2×250 g water then 297.5 g of 25% aqueous sodium chloride solution. Concentrate the organic layer to 100 g total weight below 50° C. and then add 273.0 g of acetonitrile. Concentrate the organic layer to 250 g total weight below 50° C. of title compound, tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate, which is stored as a solution: mass spectrum (m/z): 255 (M+H). Cool the mixture to −5° C.˜5° C the temperature below 5° C Stir the mixture in R1 for 0.5 hour at −5° C.˜5° C. then warm the mixture to 15˜20° C. stir for 1˜3 hours cool the mixture to 0˜10° C Add the mixture in R1 drop-wise to R2 the temperature below 10° C Warm the mixture to 20˜40° C. stir for 10-20 mins Separate the aqueous layer wash the organic layer with 2×250 g water Concentrate the organic layer to 100 g total weight below 50° C. add 273.0 g of acetonitrile Concentrate the organic layer to 250 g total weight below 50° C. of title compound, tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate, which

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

Procedure: Charge 435 g of toluene then 302.1 g of sodium bis(2-methoxyethoxy)aluminum hydride to R1. Cool the mixture to −5° C.˜5° C. Charge 652.5 g of toluene and 50 g of tert-butyl 4-(3-chloropropyl)-4-cyano-piperidine-1-carboxylate into R2 and stir the mixture until clear. Add the solution of tert-butyl 4-(3-chloropropyl)-4-cyano-piperidine-1-carboxylate in R2 drop-wise to R1, control the temperature below 5° C. Stir the mixture in R1 for 0.5 hour at −5° C.˜5° C. then warm the mixture to 15˜20° C. and stir for 1˜3 hours. Charge 25 g of sodium carbonate to R2 then add 1500 g of water and cool the mixture to 0˜10° C. Add the mixture in R1 drop-wise to R2, controlling the temperature below 10° C. Warm the mixture to 20˜40° C. and stir for 10-20 mins then allow to stand for 40-60 mins Separate the aqueous layer and wash the organic layer with 2×250 g water then 297.5 g of 25% aqueous sodium chloride solution. Concentrate the organic layer to 100 g total weight below 50° C. and then add 273.0 g of acetonitrile. Concentrate the organic layer to 250 g total weight below 50° C. of title compound, tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate, which is stored as a solution: mass spectrum (m/z): 255 (M+H). Cool the mixture to −5° C.˜5° C the temperature below 5° C Stir the mixture in R1 for 0.5 hour at −5° C.˜5° C. then warm the mixture to 15˜20° C. stir for 1˜3 hours cool the mixture to 0˜10° C Add the mixture in R1 drop-wise to R2 the temperature below 10° C Warm the mixture to 20˜40° C. stir for 10-20 mins Separate the aqueous layer wash the organic layer with 2×250 g water Concentrate the organic layer to 100 g total weight below 50° C. add 273.0 g of acetonitrile Concentrate the organic layer to 250 g total weight below 50° C. of title compound, tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate, which

Conditions: temp:76.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To commercially available 4-bromofuran-2(5H)-one (128 mg, 0.786 mmol) in THF (4 mL) was added Hunig's Base (275 μL, 1.57 mmol) and tert-butyl 3,8-diazaspiro[5,5]undecane-3-carboxylate (200 mg, 0.786 mmol). The reaction mixture was stirred at 76° C. overnight, concentrated and purified by column chromatography (0-10% MeOH in DCM) to afford the title compound. LC/MS: [(M+1)]+=337 concentrated purified by column chromatography (0-10% MeOH in DCM)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tert-butyl 4-formyl-4-propylpiperidinecarboxylate (30 g) was dissolved in a saturated solution of ammonia in methanol, and 15 g of Raney Ni was added. The reaction mixture was heated to 110° C. at 80 atmospheres pressure in a 2 L high-pressure autoclave. The mixture was filtered to remove the catalyst and the filtrate was concentrated to give residue which was purified by column chromatography to afford tert-butyl 3,8-diazaspiro[5,5]undecane-3-carboxylate. was added The mixture was filtered to remove the catalyst the filtrate was concentrated to give residue which was purified by column chromatography

Conditions: temp:76.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To commercially available 4-bromofuran-2(5H)-one (128 mg, 0.786 mmol) in THF (4 mL) was added Hunig's Base (275 μL, 1.57 mmol) and tert-butyl 3,8-diazaspiro[5,5]undecane-3-carboxylate (200 mg, 0.786 mmol). The reaction mixture was stirred at 76° C. overnight, concentrated and purified by column chromatography (0-10% MeOH in DCM) to afford the title compound. LCMS: [(M+1)]+=337 concentrated purified by column chromatography (0-10% MeOH in DCM)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tert-butyl 4-formyl-4-propylpiperidinecarboxylate (30 g) was dissolved in a saturated solution of ammonia in methanol, and 15 g of Raney Ni was added. The reaction mixture was heated to 110° C. at 80 atmospheres pressure in a 2 L high-pressure autoclave. The mixture was filtered to remove the catalyst and the filtrate was concentrated to give residue which was purified by column chromatography to afford tert-butyl 3,8-diazaspiro[5,5]undecane-3-carboxylate. was added The mixture was filtered to remove the catalyst the filtrate was concentrated to give residue which was purified by column chromatography

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

Procedure: N-Ethyl-diisopropylamine (4 eq.) was added to a solution of (3R)-3-[(2-chloro-benzoyl)amino]-2,3-dihydro-1H-indene-5-carboxylic acid (E-03) (0.952 mmol, 1 eq.) in methylene chloride (18 ml). The reaction mixture was cooled to 0° C. and N-ethyl-N′-3-(dimethylamino)-propyl-carbodiimide hydrochloride (1.2 eq.) and 1-hydroxybenzotriazole hydrate (0.2 eq.) were then added. The mixture was stirred at this temperature for 15 min, before tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate (1.1 eq.) was added. The reaction mixture was stirred at room temperature for 2.5 d. Then, the reaction mixture was washed in each case 1× with 10% NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica; ethyl acetate/hexane/ammonia (25 aq.) 70:10:0.8). Yield: 70% was added Then, the reaction mixture was washed in each case 1× with 10% NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution The organic phase was dried over sodium sulfate filtered concentrated in vacuo The crude product was purified by column chromatography (silica; ethyl acetate/hexane/ammonia (25 aq.) 70:10:0.8)