反应详情

A mechanically stirred solution of 63.67 g (300 mmol) of 5-[N-(tert-butoxycarbonyl)amino]-2-fluoropyridine, 115 mL of N,N,N′,N′-tetramethyl-ethylenediamine, and 1.8 L of dry diethyl ether was cooled to −78° C. in a Nestar refrigeration unit. n-Butyl lithium (72 mL of a 10 molar solution in hexanes) was added dropwise at such a rate so as to maintain the internal reaction temperature below −60° C. The resultant red-colored solution was stored at −40° C. for 16 hours, recooled to −78° C., then charged for ca. 20 minutes with dry carbon dioxide gas introduced via a spurge tube with the rate of bubbling adjusted so as to maintain the internal reaction temperature below −40° C. The reaction flask was removed from the bath and allowed to warm to room temperature over ca. 1 hour. The orange mixture was poured into 700 mL of cold dilute aqueous sodium hydroxide (final pH=12.5). The layers were separated, and the aqueous layer was further extracted with 2×400 mL of diethyl ether. The aqueous layer was ice cooled and acidified to ca. pH 6 with aqueous hydrochloric acid. A sticky precipitate was filtered off, then the filtrate was again ice cooled and further acidified to pH 3.0. A light yellow precipitate was collected by filtration, washed with 200 mL of water, then redissolved in 1 L of 5% aqueous sodium hydroxide. Insoluble matter was removed by filtration and the two-stage acidification/precipitation described above was repeated on the filtrate to provide 36.9 g (47%) of the dried product as a beige solid, mp 253-257° C. (dec). 1 H NMR in deuterated dimethylsulfoxide [(CD3)2SO]: δ9.83 ppm (s, 1H), 8.85 (s, 1H), 7.49 (d, JH-F=2.8 Hz, 1H), 1.48 (s, 9H).

1. temperatureto maintain the internal reaction temperature below −60° C
2. customrecooled to −78° C.
3. additionintroduced via a spurge tube with the rate
4. customof bubbling
5. temperatureto maintain the internal reaction temperature below −40° C
6. customThe reaction flask was removed from the bath
7. additionThe orange mixture was poured into 700 mL of cold dilute aqueous sodium hydroxide (final pH=12.5)
8. customThe layers were separated
9. extractionthe aqueous layer was further extracted with 2×400 mL of diethyl ether
10. temperaturecooled
11. filtrationA sticky precipitate was filtered off
12. temperaturecooled
13. filtrationA light yellow precipitate was collected by filtration
14. washwashed with 200 mL of water
15. dissolutionredissolved in 1 L of 5% aqueous sodium hydroxide
16. customInsoluble matter was removed by filtration
17. customthe two-stage acidification/precipitation