反应详情

[5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid (200 mg, 0.48 mmol), trans-4-aminocyclohexanol hydrochloride (145 mg, 0.96 mmol) and diisopropylethylamine (124 mg, 167 uL, 0.96 mmol) were dissolved in pyridine (4 mL) and stirred at room temperature10 min. EDC (184 mg) was added and the reaction was stirred at room temperature over night (16 h). Water (2 mL) was added and the resulting mixture was concentrated under reduced pressure. The resulting residue was diluted with 50 mL 1 M aqueous potassium carbonate and extracted with ethyl acetate (75+2×50 mL). The combined extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (methanol/methylene chloride gradient) to afford pure 4-[(trans-4-hydroxy-cyclohexylcarbamoyl)-methyl]-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide (148 mg, 59%) as a yellow foam. The bis-HCl salt was prepared by adding 2 equivalents of conc. HCl to an ethanolic solution of the freebase. Concentration, followed by ether trituration afforded the salt as a free-flowing, yellow powder.

1. stirringthe reaction was stirred at room temperature over night (16 h)
2. concentrationthe resulting mixture was concentrated under reduced pressure
3. additionThe resulting residue was diluted with 50 mL 1 M aqueous potassium carbonate
4. extractionextracted with ethyl acetate (75+2×50 mL)
5. washThe combined extracts were washed with water and brine
6. dry with materialdried over sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated
9. customThe crude residue was purified by silica gel chromatography (methanol/methylene chloride gradient)