tert-butyl N-(6-azaspiro[3.4]octan-8-yl)carbamate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4.1 g of 8-tert-butoxycarbonylamino-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane in 60 ml of ethanol there was added 4.5 g of 5% palladium on charcoal (50% wet) and reduction was carried out under a hydrogen atmosphere (H2 pressure: 4 atm.) for 5 hrs. During the reduction, the reaction vessel was warmed by irradiation with a tungsten lamp. At 1 hr. from the beginning of the reduction, 2 g of the same catalyst was further added and the reduction continued for an additional 4 hours at the same condition to total 5 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure to yield 2.88 g of the titled compound. for 5 hrs During the reduction, the reaction vessel was warmed by irradiation with a tungsten lamp the reduction continued for an additional 4 hours at the same condition to total 5 hours The catalyst was removed by filtration the solvent was removed under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4.1 g of 8-tert-butoxycarbonylamino-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane in 60 ml of ethanol there was added 4.5 g of 5% palladium on charcoal (50% wet) and reduction was carried out under a hydrogen atmosphere (H2 pressure: 4 atm.) for 5 hrs. During the reduction, the reaction vessel was warmed by irradiation with a tungsten lamp. At 1 hr. from the beginning of the reduction, 2 g of the same catalyst was further added and the reduction continued for an additional 4 hours at the same condition to total 5 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure to yield 2.88 g of the titled compound. for 5 hrs During the reduction, the reaction vessel was warmed by irradiation with a tungsten lamp the reduction continued for an additional 4 hours at the same condition to total 5 hours The catalyst was removed by filtration the solvent was removed under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4.1 g of 8-tert-butoxycarbonylamino-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane in 60 ml of ethanol there was added 4.5 g of 5% palladium on charcoal (50% wet) and reduction was carried out under a hydrogen atmosphere (H2 pressure: 4 atm.) for 5 hrs. During the reduction, the reaction vessel was warmed by irradiation with a tungsten lamp. At 1 hr. from the beginning of the reduction, 2 g of the same catalyst was further added and the reduction continued for an additional 4 hours at the same condition to total 5 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure to yield 2.88 g of the titled compound. for 5 hrs During the reduction, the reaction vessel was warmed by irradiation with a tungsten lamp the reduction continued for an additional 4 hours at the same condition to total 5 hours The catalyst was removed by filtration the solvent was removed under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (+/−)-tert-butyl 6-azaspiro[3.4]octan-8-ylcarbamate (from Step 1 of Example 318, 0.177 g, 0.783 mmol), 1-cyanocyclopropanecarboxylic acid (0.104 g, 0.939 mmol), EDC (0.300 g, 1.565 mmol), HOBT (0.144 g, 0.939 mmol), and Hunig's Base (0.547 mL, 3.13 mmol) in DMA (7.67 mL) was stirred @ r. t. under N2 for 16 hrs. +/−MS analysis after 16 hrs indicated that the reaction had proceeded essentially to completion and no starting material was detected. The volatiles were removed under high vacuum. EtOAc, THF, and 10% aq LiCl solution were added. The layers were separated, the organic layer was washed with 10% aq LiCl solution, 1N HCl (3×), sat. aq NaHCO3 solution (3×), brine, dried over Na2SO4, and concentrated under vacuum to yield 0.223 g of the crude product as an orange viscous semi-solid. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 4 g column), eluting with 100 mL of 75:25 hexane:EtOAc yielded 0.191 g of the title compound as a pale yellow solid. +/−MS: m/e 320.3 (M+H). 318.5 (M−H), 220.2 (M+H-Boc), 264.2 (M+H-isobutylene). This material was used in the next step without further purification. +/−MS analysis after 16 hrs indicated that the reaction The volatiles were removed under high vacuum EtOAc, THF, and 10% aq LiCl solution were added The layers were separated the organic layer was washed with 10% aq LiCl solution, 1N HCl (3×), sat. aq NaHCO3 solution (3×), brine dried over Na2SO4 concentrated under vacuum to yield 0.223 g of the crude product as an orange viscous semi-solid Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 4 g column), eluting with 100 mL of 75:25 hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (+/−)-tert-butyl 6-azaspiro[3.4]octan-8-ylcarbamate (from Step 1 of Example 318, 0.177 g, 0.783 mmol), 1-cyanocyclopropanecarboxylic acid (0.104 g, 0.939 mmol), EDC (0.300 g, 1.565 mmol), HOBT (0.144 g, 0.939 mmol), and Hunig's Base (0.547 mL, 3.13 mmol) in DMA (7.67 mL) was stirred @ r. t. under N2 for 16 hrs. +/−MS analysis after 16 hrs indicated that the reaction had proceeded essentially to completion and no starting material was detected. The volatiles were removed under high vacuum. EtOAc, THF, and 10% aq LiCl solution were added. The layers were separated, the organic layer was washed with 10% aq LiCl solution, 1N HCl (3×), sat. aq NaHCO3 solution (3×), brine, dried over Na2SO4, and concentrated under vacuum to yield 0.223 g of the crude product as an orange viscous semi-solid. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 4 g column), eluting with 100 mL of 75:25 hexane:EtOAc yielded 0.191 g of the title compound as a pale yellow solid. +/−MS: m/e 320.3 (M+H). 318.5 (M−H), 220.2 (M+H-Boc), 264.2 (M+H-isobutylene). This material was used in the next step without further purification. +/−MS analysis after 16 hrs indicated that the reaction The volatiles were removed under high vacuum EtOAc, THF, and 10% aq LiCl solution were added The layers were separated the organic layer was washed with 10% aq LiCl solution, 1N HCl (3×), sat. aq NaHCO3 solution (3×), brine dried over Na2SO4 concentrated under vacuum to yield 0.223 g of the crude product as an orange viscous semi-solid Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 4 g column), eluting with 100 mL of 75:25 hexane

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methanesulfonyl chloride (0.073 ml, 0.939 mmol) was added dropwise to a stirred solution of (+/−)-tert-butyl 6-azaspiro[3.4]octan-8-ylcarbamate (0.177 g, 0.783 mmol) in and triethylamine (0.436 ml, 3.13 mmol) in THF (9.78 mL) @ 0° C. under N2. Stirring @ 0° C. was continued for 1.5 hr. +/−MS after 1 hr 15 min looked the same as for 40 min, mostly desired product with a trace of sm. Additional methanesulfonyl chloride (0.073 ml, 0.939 mmol) was added and stirring was continued for 50 minutes. +/−MS after 40 m indicated that the reaction had proceeded essentially to completion and no starting material was detected by mass spectrum analysis (m/e 303.4, M−H for desired product). The volatile solvents were removed under vacuum. Ethyl acetate and water were added, the organic layer was washed twice with water, followed by washing with brine, and the organic layer was separated, dried (Na2SO4), and concentrated under vacuum to yield 0.231 g of the crude product as a yellow viscous semi-solid. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 4 g column), eluting with 100 mL of 1:1 hexane:EtOAc yielded 0.197 g of the title compoud as a white solid. +/−MS: m/e 303.4 (M−H). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.61 (br. s., 1H), 4.10 (br. s., 1H), 3.49 (dd, J=10.6, 5.3 Hz, 1H), 3.43-3.36 (m, 2H), 3.29 (dd, J=10.6, 3.1 Hz, 1H), 2.84 (s, 3H), 2.18-2.08 (m, 1H), 2.05-1.86 (m, 5H), 1.47 (s, 9H). @ 0° C. under N2 +/−MS after 1 hr 15 min

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methanesulfonyl chloride (0.073 ml, 0.939 mmol) was added dropwise to a stirred solution of (+/−)-tert-butyl 6-azaspiro[3.4]octan-8-ylcarbamate (0.177 g, 0.783 mmol) in and triethylamine (0.436 ml, 3.13 mmol) in THF (9.78 mL) @ 0° C. under N2. Stirring @ 0° C. was continued for 1.5 hr. +/−MS after 1 hr 15 min looked the same as for 40 min, mostly desired product with a trace of sm. Additional methanesulfonyl chloride (0.073 ml, 0.939 mmol) was added and stirring was continued for 50 minutes. +/−MS after 40 m indicated that the reaction had proceeded essentially to completion and no starting material was detected by mass spectrum analysis (m/e 303.4, M−H for desired product). The volatile solvents were removed under vacuum. Ethyl acetate and water were added, the organic layer was washed twice with water, followed by washing with brine, and the organic layer was separated, dried (Na2SO4), and concentrated under vacuum to yield 0.231 g of the crude product as a yellow viscous semi-solid. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 4 g column), eluting with 100 mL of 1:1 hexane:EtOAc yielded 0.197 g of the title compoud as a white solid. +/−MS: m/e 303.4 (M−H). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.61 (br. s., 1H), 4.10 (br. s., 1H), 3.49 (dd, J=10.6, 5.3 Hz, 1H), 3.43-3.36 (m, 2H), 3.29 (dd, J=10.6, 3.1 Hz, 1H), 2.84 (s, 3H), 2.18-2.08 (m, 1H), 2.05-1.86 (m, 5H), 1.47 (s, 9H). @ 0° C. under N2 +/−MS after 1 hr 15 min

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred solution of (+/−)-tert-butyl (6-benzyl-6-azaspiro[3.4]octan-8-yl)carbamate (Intermediate 13, 0.523 g, 1.653 mmol) in ethanol (31.2 mL) with Pd/C (10% b/w) (0.418 g, 3.14 mmol) was hydrogenated for 3 hrs 15 min @ 45 psi. +/−MS after 2 hrs 20 min indicated that the reaction was essentially complete (m/e 227.3, M+H for desired product), 171.1 (M+H-isobutylene); no starting material was detected. The catalyst was removed by filtration through a pad of Celite followed by filtration through VWR 0.45 micron Nylon filter disc. The filtrate was concentrated under vacuum, co-evaporated with CH2Cl2, to yield 0.365 g of the title compound as a viscous yellow oil which became a pale yellow solid on standing under vacuum (0.354 g). +/−MS: m/e 227.3 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.59 (br. s., 1H), 3.94 (br. s., 1H), 3.23 (dd, J=11.4, 6.2 Hz, 1H), 3.02 (d, J=11.0 Hz, 1H), 2.86 (d, J=11.0 Hz, 1H), 2.68 (dd, J=11.4, 3.7 Hz, 1H), 2.16-2.06 (m, 1H), 2.02-1.80 (m, 5H), 1.77 (d, J=2.9 Hz, 1H), 1.46 (s, 9H). +/−MS after 2 hrs 20 min

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4.1 g of 8-tert-butoxycarbonylamino-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane in 60 ml of ethanol there was added 4.5 g of 5% palladium on charcoal (50% wet) and reduction was carried out under a hydrogen atmosphere (H2 pressure: 4 atm.) for 5 hrs. During the reduction, the reaction vessel was warmed by irradiation with a tungsten lamp. At 1 hr. from the beginning of the reduction, 2 g of the same catalyst was further added and the reduction continued for an additional 4 hours at the same condition to total 5 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure to yield 2.88 g of the titled compound. for 5 hrs During the reduction, the reaction vessel was warmed by irradiation with a tungsten lamp the reduction continued for an additional 4 hours at the same condition to total 5 hours The catalyst was removed by filtration the solvent was removed under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methanesulfonyl chloride (0.073 ml, 0.939 mmol) was added dropwise to a stirred solution of (+/−)-tert-butyl 6-azaspiro[3.4]octan-8-ylcarbamate (0.177 g, 0.783 mmol) in and triethylamine (0.436 ml, 3.13 mmol) in THF (9.78 mL) @ 0° C. under N2. Stirring @ 0° C. was continued for 1.5 hr. +/−MS after 1 hr 15 min looked the same as for 40 min, mostly desired product with a trace of sm. Additional methanesulfonyl chloride (0.073 ml, 0.939 mmol) was added and stirring was continued for 50 minutes. +/−MS after 40 m indicated that the reaction had proceeded essentially to completion and no starting material was detected by mass spectrum analysis (m/e 303.4, M−H for desired product). The volatile solvents were removed under vacuum. Ethyl acetate and water were added, the organic layer was washed twice with water, followed by washing with brine, and the organic layer was separated, dried (Na2SO4), and concentrated under vacuum to yield 0.231 g of the crude product as a yellow viscous semi-solid. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 4 g column), eluting with 100 mL of 1:1 hexane:EtOAc yielded 0.197 g of the title compoud as a white solid. +/−MS: m/e 303.4 (M−H). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.61 (br. s., 1H), 4.10 (br. s., 1H), 3.49 (dd, J=10.6, 5.3 Hz, 1H), 3.43-3.36 (m, 2H), 3.29 (dd, J=10.6, 3.1 Hz, 1H), 2.84 (s, 3H), 2.18-2.08 (m, 1H), 2.05-1.86 (m, 5H), 1.47 (s, 9H). @ 0° C. under N2 +/−MS after 1 hr 15 min