(6S)-5-[(2-methylpropan-2-yl)oxycarbonyl]-5-azaspiro[2.4]heptane-6-carboxylic acid

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a degassed solution of (6S)-1,1-dibromo-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (580 mg, 1.45 mmol) in toluene (6 mL) was added the tris(trimethylsilyl)silane (1.35 mL, 4.36 mmol, 3.0 eq) and AIBN (24 mg, 0.145 mmol, 0.1 eq). The solution was heated at 110° C. for 3 hours. Another batch of tris(trimethylsilyl)silane (0.45 mL 1.45 mmol, 1.0 eq) and AIBN (10 mg) was added. The solution was heated at 110° C. for 2 more hours. A third batch of tris(trimethylsilyl)silane (0.45 mL 1.45 mmol, 1.0 eq) and AIBN (10 mg) was added. The solution was heated at 110° C. for 2 more hours. After being allowed to cool down, the solution was diluted with EtOAc (5 mL). This organic phase was extracted with aqueous K2CO3 (1 M, 10 mL×3). The combined aqueous extractions were cooled (ice/water) and acidified to pH 2 with concentrated HCl. This acidified aqueous phase was extracted with EtOAc (×3), dried (Na2SO4), filtered and evaporated. The residue was dried under vacuum to afford the desired compound as colorless oil (135 mg, 39%). The solution was heated at 110° C. for 2 more hours The solution was heated at 110° C. for 2 more hours to cool down This organic phase was extracted with aqueous K2CO3 (1 M, 10 mL×3) The combined aqueous extractions were cooled (ice/water) This acidified aqueous phase was extracted with EtOAc (×3) dried (Na2SO4) filtered evaporated The residue was dried under vacuum

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

実験手順: To a solution of (S)-5-tert-butyl 6-methyl 5-azaspiro[2.4]heptane-5,6-dicarboxylate (0.436 g, 1.708 mmol) in ethanol (4 mL) was added a solution of LiOH.H2O (86.0 mg, 2.049 mmol, 1.2 eq) in H2O (2 mL) at room temperature. The mixture was stirred at room temperature for 20 hours. EtOH was removed by rotavapor. The aqueous residue was diluted with H2O and extracted with Et2O. The aqueous layer was cooled with an ice bath and acidified to pH ˜2 with 1 N HCl. The resulting milky solution was extracted with a mixed solvent of EtOAc and CH2Cl2. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was dried under vacuum to afford the desired product as an off-white solid (0.422 g, 100%). EtOH was removed by rotavapor The aqueous residue was diluted with H2O extracted with Et2O The aqueous layer was cooled with an ice bath The resulting milky solution was extracted with a mixed solvent of EtOAc and CH2Cl2 The organic layer was dried (Na2SO4) filtered evaporated The residue was dried under vacuum

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of (6S)-1,1-dibromo-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (8.7 g, 21.8 mmol), 50 wt % hypophosphorus acid (25.9 mL, 9 eq) and triethylamine (44.3 mL, 10 eq) in water (104 mL, 12 volumes) was added V-50 (591 mg, 0.1 eq) in 2 mL of 50% aqueous acetonitrile. The mixture was heated at 100° C. During the heating, additional 0.1 eq of V-50 was added to the reaction mixture every 30 minutes. Totally, 0.7 eq of V-50 was added. After heating at 100° C. for 4 hrs, the reaction mixture was evaporated and treated with 2N NaOH. It was extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified with 2N HCl, extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated to give the title compound (3.63 g, 69%) as a light yellow solid. 1H NMR (500 MHz, CDCl3): 4.51-4.42 (m, 1H), 3.48-3.11 (m, 2H), 2.27-1.93 (m, 2H), 1.50/1.45 (two overlapping s, 9H), 0.71-0.59 (m, 4H). During the heating, additional 0.1 eq of V-50 was added to the reaction mixture every 30 minutes Totally, 0.7 eq of V-50 was added After heating at 100° C. for 4 hrs the reaction mixture was evaporated treated with 2N NaOH It was extracted with ethyl acetate (2×50 mL) extracted with ethyl acetate (2×50 mL) The combined organic layers were washed with water and brine dried (Na2SO4) filtered evaporated