反应详情

A mixture of 2,2,3,3-tetramethyl-cyclopropanecarboxylic acid (50 mg, 0.35 mmol), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU) (145 mg, 0.35 mmol), N-ethyldiisopropylamine (171 μL, 1 mmol) in CH2Cl2 (3 mL) is stirred for 10 min at RT. After the addition of (3R*,5S*)-3-amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (121.4 mg, 0.2 mmol) (Starting Material 6), stirring is continued for 14 h. The mixture is diluted with CH2Cl2, the organic layer washed with saturated NaHCO3 solution, dried over Na2SO4 and evaporated in vacuo. The crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (5 mL) for 2 h, the mixture is evaporated and the residue purified by preparative HPLC (C18 column, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a yellowish solid. MS: 509.6 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.68 min.

1. stirringstirring
2. waitis continued for 14 h
3. washthe organic layer washed with saturated NaHCO3 solution
4. dry with materialdried over Na2SO4
5. customevaporated in vacuo
6. stirringThe crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (5 mL) for 2 h
7. customthe mixture is evaporated
8. customthe residue purified by preparative HPLC (C18 column, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min)
9. additionThe combined pure fractions are treated with K2CO3, CH3CN
10. customis removed in vacuo
11. extractionthe residual aqueous phase is extracted three times with CH2Cl2
12. dry with materialThe combined organic layers are dried (Na2SO4)
13. customevaporated