反应详情

温度

0 °C

To a stirred, ice-cooled mixture of (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (300 mg, 0.643 mmol) in CH2Cl2 (7 mL) a 2M solution of N-ethyldiisopropylamine in 1-methyl-2-pyrrolidone (161 μl, 0.322 mmol) is added, followed by a solution of O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU) (292 mg, 0.707 mmol) in CH3CN (7 mL). After 15 min cyclopropyl-(2,3-dichloro-benzyl)-amine (139 mg, 0.643 mmol) is added. The mixture is stirred for 15 min at 0° C. and for 14 h at RT. After evaporation of the solvents in vacuo, the residue is diluted with CH2Cl2 and washed with a 10% aqueous K2CO3 solution, 2M HCl solution and brine. The organic layer is dried over Na2SO4, evaporated in vacuo and the residue purified by flash chromatography (SiO2, CH2Cl2/acetone 96:4). Part of the crude product (50 mg, 0.075 mmol) is dissolved in CH2Cl2 (1 mL), treated with piperidine (0.222 mL, 2.25 mmol) and stirred for 1 h at RT. After evaporation in vacuo, the residue is purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with solid K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a colourless foam. MS: 442.2/444.2 [M+H]+; tR (HPLC, Lichrospher RP8; 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min, then 100% CH3CN+0.1% TFA for 2.5 min, flow 1.5 ml/min): 5.08 min.

1. temperatureTo a stirred, ice-cooled
2. additionis added
3. customAfter evaporation of the solvents in vacuo
4. additionthe residue is diluted with CH2Cl2
5. washwashed with a 10% aqueous K2CO3 solution, 2M HCl solution and brine
6. dry with materialThe organic layer is dried over Na2SO4
7. customevaporated in vacuo
8. customthe residue purified by flash chromatography (SiO2, CH2Cl2/acetone 96:4)
9. stirringstirred for 1 h at RT
10. customAfter evaporation in vacuo
11. customthe residue is purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min)
12. additionThe combined pure fractions are treated with solid K2CO3, CH3CN
13. customis removed in vacuo
14. extractionthe residual aqueous phase is extracted twice with CH2Cl2
15. dry with materialThe combined organic layers are dried (Na2SO4)
16. customevaporated