反应详情

A vial was charged with D,L-azetidine-2-carboxylic acid (56 mg, 0.56 mmol) and DMF (1 mL). Then NaH (60% dispersion in mineral oil, 33 mg, 0.84 mmol) was added slowly (gas evolution). After 2 min. of stirring at room temperature was added 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456). The heterogeneous white reaction mixture was stirred and heated at 120° C. After overnight stirring the reaction mixture was cooled to rt and was diluted in EtOAc (5 mL). The mixture was poured into a reparatory funnel with 0.5M HCl (1 mL) and water (5 mL). The aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and concentrated in-vacuo. The crude was purified by silica gel column chromatography, eluted with dichloromethane in methanol (9:1) to produce 7.7 mg (6% yield) of 1-[5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-azetidine-2-carboxylic acid (P-446) as a cream solid.

1. stirringThe heterogeneous white reaction mixture was stirred
2. temperatureheated at 120° C
3. stirringAfter overnight stirring the reaction mixture
4. temperaturewas cooled to rt
5. extractionThe aqueous layer was extracted with EtOAc (3×5 mL)
6. washThe combined organic layers were washed with brine (15 mL)
7. dry with materialdried over Na2SO4
8. concentrationconcentrated in-vacuo
9. customThe crude was purified by silica gel column chromatography
10. washeluted with dichloromethane in methanol (9:1)