4-Chloro-2-methylpyridine → 2-Fluoro-4-(2-methylpyridin-4-yloxy)phenylamine

A solution of 4-amino-3-fluorophenol (5.00 g, 39.3 mmol) in anhydrous DMA (100 mL) was treated with potassium tert-butoxide (5.30 g, 47.2 mmol), and the red-brown mixture was stirred at room temperature for 1 h. The mixture was treated with a solution of 4-chloro-2-picoline (5.02 g, 39.3 mmol) in anhydrous DMA (75 mL) and then heated at 100° C. for 17 h. The mixture was cooled to ambient temperature and partitioned between EtOAc (500 mL) and saturated NaCl solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated at reduced pressure. Purification through a silica gel plug, eluting with 40% EtOAc/hexane, followed by crystallization from DCM/hexane afforded 4.06 g (47%) of the title compound as a yellow solid. 1H-NMR (DMSO-d6) δ 8.24 (d, J=5.4 Hz, 1H), 6.91 (dd, J=12.3, 2.7 Hz, 1H), 6.80 (dd, J=9.6, 8.7 Hz, 1H), 6.72 to 6.62 (m, 3H), 5.15 (broad s, 2H), (2.36 (s, 3H); MS LC-MS [M+H]+=219, RT=0.24 min.

1. temperatureheated at 100° C. for 17 h
2. temperatureThe mixture was cooled to ambient temperature
3. custompartitioned between EtOAc (500 mL) and saturated NaCl solution (500 mL)
4. extractionThe aqueous phase was back-extracted with EtOAc (300 mL)
5. washThe combined organic phases were washed with brine
6. dry with materialdried over Na2SO4
7. concentrationconcentrated at reduced pressure
8. customPurification through a silica gel plug
9. washeluting with 40% EtOAc/hexane
10. customfollowed by crystallization from DCM/hexane

ORD-Eintrag

ord-38e4b247f59b4dbdbab866525d5b44ae

Quelldatensatz

uspto-grants-2012_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08207166B2