Diisopropylethylamine → (R)-2-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-succinamic acid

Participants

Reaction Steps

2-Chlorotrityl resin (0.536 g, 0.75 mmol/g) was placed in a dry glass fritted shaker flask. To the resin was added CH2Cl2 (10 mL), diisopropylethylamine (0.522 mL) and Fmoc-L-asparagine (0.265 g, 0.75 mmol) and the reaction was agitated on an orbital shaker for 14 h. The reaction solution was drained and the resin washed with CH2Cl2/MeOH/DIEA (17:2:1; 3×10 mL), CH2Cl2 (3×10 mL), DMF (3×10 mL), and CH2Cl2 (3×10 mL). The resin was swelled with DMF (2 mL) and the solvent drained. A solution of 50% piperidine in DMF (10 mL) was added to the resin and the reaction was agitated on an orbital shaker for 90 min. The reaction solution was drained and the resin washed with DMF (2×10 mL), CH2Cl2 (2×10 mL), DMF (2×10 mL), CH2Cl2 (2×10 mL), and DMA (1×2 mL). (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (0.132 g, 0.30 mmol) and HATU (0.285 g, 0.75 mmol) were dissolved in DMA (2 mL), and the resulting solution added to the resin. Diisopropylethylamine (0.130 mL, 0.75 mmol) was added and the reaction agitated on an orbital shaker for 48 h. The reaction solution was drained and washed as described above. The resin was treated with 10% TFA in CH2Cl2 and agitated on an orbital shaker for 90 min. The reaction solution was collected and the resin washed with CH2Cl2 (4×3 mL). The filtrates were combined with the supernatant and the volatiles removed in vacuo at 40° C. The residue was dissolved in CH2Cl2 (5 mL) and washed with water (2×5 mL) and brine (5 mL). The organic layer was dried over anhydrous Na2SO4, the solution decanted, and the solvent removed in vacuo to afford 0.122 g (73%) of (R)-2-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-succinamic acid as an orange foam.

Provenance & Evidence