Iodine → 1,1-Dimethylethyl N-(4-fluoro-3-iodo-2-pyridinyl)carbamate

Temperatur

-78 °C

An oven-dried 3-neck round bottom flask equipped with an overhead stirrer, temperature probe, and addition funnel was charged with tert-butyl (4-fluoropyridin-2-yl)carbamate (Int-26, 31.8 g, 150 mmol), TMEDA (56.6 mL, 375 mmol) and THF (200 mL). The solution was cooled to −78° C. and a solution of n-butyllithium (2.50 M in hexane, 150 mL, 375 mmol) was added dropwise such that the reaction mixture temperature remained below −70° C. Upon completion of addition, the reaction mixture was stirred at −78° C. for 1 h, and a solution of I2 (95.2 g, 375 mmol) in THF (160 mL) was added via addition funnel. The addition was again controlled to keep the reaction mixture temperature below −70° C., and the resulting mixture was stirred at −78° C. for 1 h. A solution of NaHSO3 (61 g, 580 mmol) in water (200 mL) was added to the reaction mixture as it warmed to room temperature. Ethyl acetate was added and the biphasic mixture was stirred at room temperature for 1 h. Water (500 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (3×400 mL); the organic phases were combined, dried over magnesium sulfate, filtered and concentrated to give an off-white solid. This solid was suspended in methylene chloride (50 mL) and the solid was isolated by suction filtration and washed with a minimum of methylene chloride. The filtrate was concentrated and filtered to give a second crop of product. The solids were combined and dried under vacuum to give tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate as a white solid (45.63 g, 86% yield). LC-MS: (FA) ES+ 339. 1H NMR (400 MHz, d6-DMSO) δ ppm 9.47 (s, 1H), 8.32 (dd, J=8.9, 5.5 Hz, 1H), 7.18 (dd, J=7.2, 5.5 Hz, 1H), 1.44 (s, 9H).

1. customAn oven-dried 3-neck round bottom flask equipped with an overhead stirrer
2. additiontemperature probe, and addition funnel
3. customremained below −70° C
4. additionUpon completion of addition
5. additionThe addition
6. customthe reaction mixture temperature below −70° C.
7. stirringthe resulting mixture was stirred at −78° C. for 1 h
8. temperaturewarmed to room temperature
9. stirringthe biphasic mixture was stirred at room temperature for 1 h
10. customthe phases were separated
11. extractionThe aqueous phase was extracted with EtOAc (3×400 mL)
12. dry with materialdried over magnesium sulfate
13. filtrationfiltered
14. concentrationconcentrated
15. customto give an off-white solid
16. customthe solid was isolated by suction filtration
17. washwashed with a minimum of methylene chloride
18. concentrationThe filtrate was concentrated
19. filtrationfiltered
20. customto give a second crop of product
21. customdried under vacuum

ORD-Eintrag

ord-200708c71944412fa9c503377dbfa7e9

Quelldatensatz

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08513421B2