反应详情

A solution of 158 mg (0.5 mmol) of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1), 96 mg (0.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 89 mg (0.63 mmol based on 95% purity) of 1-hydroxybenzotriazole (HOBT) in 4 mL of anhydrous dichloromethane was stirred at room temperature in a stoppered flask. After 15-20 min, this solution was added dropwise by syringe through a septum to a second solution of 95.5 mg (0.6 mmol) of 1-hydrazinoisoquinoline (Intermediate 8) and 0.261 mL (194 mg, 1.5 mmol) of N,N-diisopropylethylamine in 2 mL of anhydrous dichloromethane and 2 mL of anhydrous DMF. Stirring under nitrogen was continued for 4 h. The solution was then concentrated under vacuum. The residue was partitioned between ethyl acetate and 5% aqueous citric acid solution. The organic phase was washed with more 5% citric acid, then with water, and finally with saturated sodium carbonate aqueous solution. The organic solution was dried over magnesium sulfate, filtered and concentrated. The residue contained the title compound along with some material that had already undergone ring closure. LC-MS 457 (M+1 for title compound), 439 (M+1 for ring-closed product).

1. waitwas continued for 4 h
2. concentrationThe solution was then concentrated under vacuum
3. customThe residue was partitioned between ethyl acetate and 5% aqueous citric acid solution
4. washThe organic phase was washed with more 5% citric acid
5. dry with materialThe organic solution was dried over magnesium sulfate
6. filtrationfiltered
7. concentrationconcentrated
8. customLC-MS 457 (M+1 for title compound), 439 (M+1 for ring-closed product)