反应详情

Combine 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.7 g, 6.8 mmol, Reference J. Med. Chem. 1998, 41 (25), 4983-4994), cesium carbonate (4.4 g, 13.6 mmol) and N,N-dimethylformamide (75 mL) and stir at room temperature for 30 minutes. Add 6-chloronicotinamide (1.1 g, 6.8 mmol) and heat at 100° C. for 2 days. Cool to room temperature, dilute with brine then extract with ethyl acetate (3× 125 mL). Dry the ethyl acetate extracts with sodium chloride/magnesium sulfate, filter, then concentrate on a rotary evaporator to yield 12 g of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with (0.1% conc. ammonium hydroxide/1% ethanol) to (1% conc. ammonium hydroxide/10% ethanol) in chloroform to yield 7-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.2 g, 3.3 mmol): 1H NMR (CDCl3, 300.00 MHz): 8.59 (s, 1H); 8.17 (d, 1H); 7.20-7.17 (m, 2H); 6.98-6.89 (m, 2H); 5.97 (s, 2H); 4.57 (s, 2H); 3.68-3.66 (m, 2H); 2.83 (t, 2H); 1.48 (s, 9H).

1. extractionthen extract with ethyl acetate (3× 125 mL)
2. dry with materialDry the ethyl acetate
3. filtrationfilter
4. concentrationconcentrate on a rotary evaporator
5. customto yield 12 g of the crude product
6. customThe crude product is purified by flash column chromatography on silica gel eluting with (0.1% conc. ammonium hydroxide/1% ethanol) to (1% conc. ammonium hydroxide/10% ethanol) in chloroform