ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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: In a 50 ml round-bottomed flask, (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (813 mg, 4.64 mmol) was combined with DMF (10 ml) to give a colorless solution. HATU (1.76 g, 4.64 mmol) was added and stirred at room temperature for 10 min. Ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate (prepared according to the patent procedure described in WO 199808850) (900 mg, 4.22 mmol) and DIPEA (1.91 g, 2.58 ml, 14.8 mmol) were added and stirred overnight. It was diluted with H2O and extracted with EtOAc (2×100 ml). The organic layer was washed with brine and H2O, dried with MgSO4, filtered and concentrated in vacuo to afford (S)-ethyl 2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-8-oxa-2-azaspiro[4.5]decane-3-carboxylate as a viscous oil (1.3 g, 83.2%). ESI-LRMS m/e calcd for C18H30N2O6 [M+] 370. found 371 [M+H+]. to give a colorless solution were added stirred overnight extracted with EtOAc (2×100 ml) The organic layer was washed with brine and H2O dried with MgSO4 filtered concentrated in vacuo

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

実験手順: Ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate (3.54 g, 16.6 mmol) was dissolved in dry dichloromethane (80 mL), triethylamine (5.8 mL, 41.5 mmol) was added followed by benzylchloroformate (3.5 mL, 24.9 mmol) and the reaction is stirred at room temperature for 2 h under nitrogen. The reaction was diluted with dichloromethane, washed with 0.2 N HCl, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20-100% hexanes/EtOAc to afford a yellow oil. The racemate was then separated by chiral HPLC on a 10 μm OD column eluting with 25% isopropanol in hexanes to afford the title compound as a clear oil (1.66 g, 29% yield). washed with 0.2 N HCl dried over MgSO4 concentrated in vacuo The residue was purified by silica gel chromatography eluting with 20-100% hexanes/EtOAc to afford a yellow oil The racemate was then separated by chiral HPLC on a 10 μm OD column eluting with 25% isopropanol in hexanes

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

実験手順: Ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate (3.54 g, 16.6 mmol) was dissolved in dry dichloromethane (80 mL), triethylamine (5.8 mL, 41.5 mmol) was added followed by benzylchloroformate (3.5 mL, 24.9 mmol) and the reaction is stirred at room temperature for 2 h under nitrogen. The reaction was diluted with dichloromethane, washed with 0.2 N HCl, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20-100% hexanes/EtOAc to afford a yellow oil. The racemate was then separated by chiral HPLC on a 10 μm OD column eluting with 25% isopropanol in hexanes to afford the title compound as a clear oil (1.66 g, 29% yield). washed with 0.2 N HCl dried over MgSO4 concentrated in vacuo The residue was purified by silica gel chromatography eluting with 20-100% hexanes/EtOAc to afford a yellow oil The racemate was then separated by chiral HPLC on a 10 μm OD column eluting with 25% isopropanol in hexanes

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

実験手順: To a solution of ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate (101) (200 mg, 0.94 mmol), HATU (392 mg, 1.03 mmol) and N-[(methyloxy)carbonyl]-L-valine (181 mg, 1.03 mmol) in anhydrous CH2Cl2 (6 mL) was added Hunig's base (0.33 mL, 1.88 mmol) and the solution stirred at rt under nitrogen. After 2 h, the reaction was concentrated in vacuo, purified by C18 RP chromatography, eluting with 10-90% ACN/water/0.2% NH4OH, to afford the product as a yellow oil (313 mg, 90% yield). the reaction was concentrated in vacuo purified by C18 RP chromatography eluting with 10-90% ACN/water/0.2% NH4OH

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

実験手順: Ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate (3.54 g, 16.6 mmol) was dissolved in dry dichloromethane (80 mL), triethylamine (5.8 mL, 41.5 mmol) was added followed by benzylchloroformate (3.5 mL, 24.9 mmol) and the reaction is stirred at room temperature for 2 h under nitrogen. The reaction was diluted with dichloromethane, washed with 0.2 N HCl, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20-100% hexanes/EtOAc to afford a yellow oil. The racemate was then separated by chiral HPLC on a 10 μm OD column eluting with 25% isopropanol in hexanes to afford the title compound as a clear oil (1.66 g, 29% yield). washed with 0.2 N HCl dried over MgSO4 concentrated in vacuo The residue was purified by silica gel chromatography eluting with 20-100% hexanes/EtOAc to afford a yellow oil The racemate was then separated by chiral HPLC on a 10 μm OD column eluting with 25% isopropanol in hexanes

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

実験手順: Ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate (3.54 g, 16.6 mmol) was dissolved in dry dichloromethane (80 mL), triethylamine (5.8 mL, 41.5 mmol) was added followed by benzylchloroformate (3.5 mL, 24.9 mmol) and the reaction is stirred at room temperature for 2 h under nitrogen. The reaction was diluted with dichloromethane, washed with 0.2 N HCl, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20-100% hexanes/EtOAc to afford a yellow oil. The racemate was then separated by chiral HPLC on a 10 μm OD column eluting with 25% isopropanol in hexanes to afford the title compound as a clear oil (1.66 g, 29% yield). washed with 0.2 N HCl dried over MgSO4 concentrated in vacuo The residue was purified by silica gel chromatography eluting with 20-100% hexanes/EtOAc to afford a yellow oil The racemate was then separated by chiral HPLC on a 10 μm OD column eluting with 25% isopropanol in hexanes

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

実験手順: To a solution of ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate (101) (200 mg, 0.94 mmol), HATU (392 mg, 1.03 mmol) and N-[(methyloxy)carbonyl]-L-valine (181 mg, 1.03 mmol) in anhydrous CH2Cl2 (6 mL) was added Hunig's base (0.33 mL, 1.88 mmol) and the solution stirred at rt under nitrogen. After 2 h, the reaction was concentrated in vacuo, purified by C18 RP chromatography, eluting with 10-90% ACN/water/0.2% NH4OH, to afford the product as a yellow oil (313 mg, 90% yield). the reaction was concentrated in vacuo purified by C18 RP chromatography eluting with 10-90% ACN/water/0.2% NH4OH

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 ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate (101) (200 mg, 0.94 mmol), HATU (392 mg, 1.03 mmol) and N-[(methyloxy)carbonyl]-L-valine (181 mg, 1.03 mmol) in anhydrous CH2Cl2 (6 mL) was added Hunig's base (0.33 mL, 1.88 mmol) and the solution stirred at rt under nitrogen. After 2 h, the reaction was concentrated in vacuo, purified by C18 RP chromatography, eluting with 10-90% ACN/water/0.2% NH4OH, to afford the product as a yellow oil (313 mg, 90% yield). the reaction was concentrated in vacuo purified by C18 RP chromatography eluting with 10-90% ACN/water/0.2% NH4OH