反应详情

To a stirred, ice-cooled mixture of (3R*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (233 mg, 0.5 mmol), cyclopropyl-(2,3-dichloro-benzyl)-amine (112 mg, 0.52 mmol) and N-ethyldiisopropylamine (685 μL, 4 mmol) in dimethylacetamide (3 mL), propylphosphonic anhydride solution (˜50% in DMF, 0.48 mL, ˜0.75 mmol) is added. The mixture is stirred for 14 h at RT. After evaporation of the solvent in vacuo, the residue is diluted with ethyl acetate and washed with a 10% aqueous K2CO3 solution and brine. The organic layer is dried over Na2SO4, evaporated in vacuo and the residue 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 (3R*,5R*)-3-tert-butoxycarbonylamino-5-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester as a colourless oil. tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, then 100% CH3CN+0.1% TFA for 2 min, flow 1.5 ml/min): 8.45 min. The product is dissolved in CH2Cl2/piperidine 4:1 (5 mL) 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, 30 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 resin. MS: 442.3/444.2 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.58 min.

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